biology
Re iew
Mi ochond ial mic oRNAs: A Pu a i e Role in
Tissue Regene a ion
Síl ia C. Rod igues 1,2,3 , Rena o M. S. Ca doso 4and Filipe V. Dua e 3,*
1Exogenus The apeu ics, 3060-197 Can anhede, Po ugal; [email p o ec ed]
2Doc o al P og amme in Expe imen al Biology and Biomedicine (PDBEB), Ins i u e o In e disciplina y
Resea ch (IIIUC), Uni e si y o Coimb a, 3004-504 Coimb a, Po ugal
3CNC—Cen e o Neu oscience and Cell Biology, Uni e si y o Coimb a, 3004-504 Coimb a, Po ugal
4Lase Leap Technologies, 3025-307 Coimb a, Po ugal; [email p o ec ed]
*Co espondence: [email p o ec ed]
Recei ed: 16 No embe 2020; Accep ed: 19 Decembe 2020; Published: 21 Decembe 2020

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Simple Summa y:
Dis inc issue enginee ing s a egies a e cu en ly being de eloped. Cell-based
he apies, implan a ion o syn he ic sca olds o combina ion o a sca old wi h seeded cells a e being
used acco ding o he biologic p emises. Mi ochond ia play a cen al ole in cell li e cycle due o
hei p eponde an ole in ene gy p oduc ion. Recen da a sugges ha small non-coding RNAs
encoded by mi ochond ia DNA such as mic oRNAs egula e a ple ho a o ac o s and consequen ly
signaling pa hways, c ucial in disease pa hogenesis and also pu a i ely in egene a i e p ocesses.
Un eiling mi ochond ial mic oRNAs biological unc ion and hei a ge s will p opel he de elopmen
o inno a i e he apeu ic and diagnos ic ools.
Abs ac :
The mos amous ole o mi ochond ia is o gene a e ATP h ough oxida i e phospho yla ion,
a me abolic pa hway ha in ol es a chain o ou p o ein complexes ( he elec on anspo chain,
ETC) ha gene a es a p o on-mo i e o ce ha in u n d i es he ATP syn hesis by he Complex
V (ATP syn hase). An imp essi e numbe o mo e han 1000 mi ochond ial p o eins ha e been
disco e ed. Since mi ochond ial p o eins ha e a dual gene ic o igin, i is p edic ed ha ~99% o hese
p o eins a e nuclea -encoded and a e syn hesized in he cy oplasma ic compa men , being u he
impo ed h ough mi ochond ial memb ane anspo e s. The las ing 1% o mi ochond ial p o eins a e
encoded by he mi ochond ial genome and syn hesized by he mi ochond ial ibosome (mi o ibosome).
As a esul , an app op ia e egula ion o mi ochond ial p o ein syn hesis is absolu ely equi ed o
achie e and main ain no mal mi ochond ial unc ion. Rega ding miRNAs in mi ochond ia, i is
well- ecognized nowadays ha se e al cellula mechanisms in ol ing mi ochond ia a e egula ed by
many gene ic playe s ha o igina e om ei he nuclea - o mi ochond ial-encoded small noncoding
RNAs (sncRNAs). G owing e idence collec ed om whole genome and ansc ip ome sequencing
highligh he ole o dis inc membe s o his class, om sho in e e ing RNAs (siRNAs) o miRNAs
and long noncoding RNAs (lncRNAs). Some o he mechanisms ha ha e been shown o be modula ed
a e he exp ession o mi ochond ial p o eins i sel , as well as he mo e complex coo dina ion o
mi ochond ial s uc u e and dynamics wi h i s unc ion. We de o e pa icula a en ion o he ole o
mi ochond ial miRNAs and o hei ole in he modula ion o se e al molecula p ocesses ha could
ul ima ely con ibu e o issue egene a ion accomplishmen .
Keywo ds: mic oRNA; mi ochond ia; mi omiRs; issue egene a ion
Biology 2021,9, 486; doi:10.3390/biology9120486 www.mdpi.com/jou nal/biology
Biology 2021,9, 486 2 o 18
1. Regene a i e Biology
Regene a ion is he abili y o animals o es o e, ei he pa ially o en i ely, issues o o gans
ha we e damaged due o auma [
1
]. This egene a i e capaci y s ongly a ies along he animal
kingdom and, while some species can egene a e he whole body om jus small agmen s (hyd a and
plana ia), he e a e o he species, such as mammals, ha ha e a poo egene a i e capaci y, and a
p o ound damage gene ally esul s in sca ing [
2
,
3
]. Since he 18 h cen u y, e olu iona y biologis s
ha e been ying o disclose he mechanisms unde lying he issue egene a ion in animals wi h a
highe egene a i e capaci y han humans, such as salamande s [
4
] and zeb a ish [
5
,
6
]. This di e si y in
he egene a i e capaci y ac oss animal species is a ibu ed o di e en issue epai mechanisms ha
can be classi ied in wo ca ego ies: mo phallaxis and epimo phosis [
7
]. While he i s is common in
lowe species, he la e is usually obse ed in highe o de species being a ibu ed o he egene a ion
o he damaged issue h ough a local cell p oli e a ion mechanism (blas ema) which does no a ec
he emaining o ganism [
8
]. The epimo phic egene a ion has been widely s udied in salamande s,
zeb a ish and o he species and i in ol es di e en s ages ha a e ini ia ed a e an inju y and
culmina ed wi h he pe ec egene a ion o he issue o o gan. In i s ini ial s ages, he epimo phic
egene a ion is e y simila o a wound-healing mechanism. A e inju y, he e is he hemos asis phase
ollowed by a e-epi heliza ion p ocess in he damage epide mis (mig a ion o he ke a inocy es o he
inju ed ci e) [
8
]. As he e-epi heliza ion is comple e, he egene a ion s age s a s wi h he o ma ion o
a mass, composed o he e ogeneous undi e en ia ed cell popula ions (blas ema), and hose cells ha e
he capaci y o di e en ia e in speci ic cells ha a e equi ed o comple e he epai o he issue [
9
].
The e a e some simila i ies be ween epimo phic egene a ion and sca o ma ion: hey a e bo h
igge ed by a hemos a ic p ocess and he e is a e-epi heliza ion p ocess o co e he wounded a ea,
wi h he o ma ion o blas ema being he main di e ence be ween bo h egene a i e p ocesses. I is
known ha in mos mammals, he egene a i e p ocess s alls in he ea ly s ages o wound healing and
hen mo es owa ds a ib o ic epai and sca o ma ion [
9
]. Conside ing his, he ul ima e goal o
egene a i e medicine is he s imula ion o a blas ema ha would ul ima ely d i e he healing p ocess
owa ds egene a ion ins ead o sca ing. Al hough he o e all capaci y o mammals, namely humans,
is somewha limi ed, hei o gans ha e di e en ial sel - enewal capaci ies and, while some o gans
con inuously egene a e, like blood and skin, o he s can egene a e a e inju y, such as li e and bone,
and o he s ha e a es ic ed egene a ion capaci y, like he hea and kidneys [10].
Clinical App oaches
Cu en ly, he e a e h ee di e en app oaches in egene a i e medicine: (i) cell-based he apies,
(ii) implan a ion o syn he ic sca olds o epai and (iii) combina ion o a sca old wi h seeded cells [
11
],
as depic ed in Figu e 1. Cell he apy consis s in he injec ion a he inju ed si e o ei he di e en ia ed
cells o undi e en ia ed s em cells o econs i u e he damaged issue. S em cells, due o hei abili y o
di e en ia e in o se e al cell ypes, eme ged as a undamen al ool in egene a i e medicine. Ini ially,
he he apeu ic po en ial o s em cells was a ibu ed o hei capaci y o di e en ia e in issue-speci ic
cells, he e o e p omo ing issue egene a ion. Nowadays, i is known ha s em cells also ac i ely
sec e e a b oad a ie y o biomolecules (cy okines, chemokines, g ow h ac o s) ha ei he ac on
neighbo ing cells (pa ac ine e ec ) o on hemsel es (au oc ine) o p omo e issue epai .
In egene a i e medicine, human s em cells can be classi ied in o issue-speci ic p ogeni o s em
cells (TSPSCs), emb yonic s em cells (ESCs), umbilical co d s em cells (UCSCs), mesenchymal s em
cells (MSCs) and induced plu ipo en s em cells (iPSCs) [
12
]. The ESCs a e capable o di e en ia ion
in o mesode mal, endode mal and ec ode mal cell lineages, and ha makes hem ou s anding ools
o egene a i e medicine [
13
]. Acco ding o he li e a u e, he ansplan a ion o hESCs o pa ien s
wi h spinal co d inju y (SCI) imp o es sensa ion, body con ol and o e all limb mo emen [
14
].
Mo eo e , ESCs-de i ed ca dio ascula p ogeni o cells egene a e ca diac issue, p o iding i s
mechanical epai [
15
,
16
]. ESCs-de i ed hepa ocy es ha e been success ully accomplished and hey
a e an impo an ool o d ug sc eening and cell he apy [
17
]. The ansplan a ion o ESCs-de i ed
Biology 2021,9, 486 3 o 18
chond ocy es e ec i ely heals knee join de ec s [
18
]. Al hough ESCs ha e eme ged as a p omising
ool in egene a i e medicine, hei use in esea ch has been highly deba ed due o e hical conce ns [
19
].
TSPSCs, in opposi ion o ESCs, gi e ise o speci ic ypes o cells; mo eo e , hei numbe is limi ed,
making collec ion and
in i o
expansion ex emely di icul . When ac i a ed by a signal deli e y,
TSPSCs s a o p oli e a e and mig a e o he inju y si e, whe e hey di e en ia e and acqui e a
speci ic pheno ype con ibu ing o issue epai and enewal. In a clinic en i onmen , a posi i e
co ela ion be ween long- e m me abolic success upon ansplan a ion o panc ea ic p ogeni o cells
was demons a ed, p o ing ha despi e hei limi a ions, he cells ha e an impo an egene a i e
capaci y (induc ion o expandable issue-speci ic p ogeni o cells om human). The MSCs ha e
eme ged as a e sa ile and widely used he apeu ic ool in egene a i e medicine. They a e ound in
se e al
in i o
loca ions such as bone ma ow, skin, panc eas, hea , b ain, lung and o he s [
20
–
22
],
and can be easily expanded wi hou losing hei mul ipo ency capaci y. MSCs, when exposed o speci ic
ac o s, can unde go a ilineage di e en ia ion: os eogenesis, adipogenesis and chond ogenesis [
23
];
howe e , he di e en ia ion owa ds o he cell ypes has also been epo ed in he li e a u e [
24
].
The umbilical co d blood p o ides an immune-compa ible sou ce o s em cells ha is easily and sa ely
collec ed and s o ed by UCB banks [
25
]. Mo eo e , UCBSCs ha e also been conside ed as an al e na i e
o ESCs due o hei con en in mul ipo en s em cells, able o di e en ia e in se e al cell ypes [
26
].
Cu en ly, he egene a i e capaci y o UCBSCs has been desc ibed o se e al diseases ha include
neu onal inju y [27], ca diac in a c ion [28] and bone egene a ion [29].
Biology 2020, 9, 486 3 o 19
Figu e 1. Depic ion o he cu en clinical/ he apeu ic app oaches o issue egene a ion: cell-based
he apies, implan a ion o syn he ic sca olds o epai and combina ion o a sca old wi h seeded
cells.
In egene a i e medicine, human s em cells can be classi ied in o issue-speci ic p ogeni o s em
cells (TSPSCs), emb yonic s em cells (ESCs), umbilical co d s em cells (UCSCs), mesenchymal s em
cells (MSCs) and induced plu ipo en s em cells (iPSCs) [12]. The ESCs a e capable o di e en ia ion
in o mesode mal, endode mal and ec ode mal cell lineages, and ha makes hem ou s anding ools
o egene a i e medicine [13]. Acco ding o he li e a u e, he ansplan a ion o hESCs o pa ien s
wi h spinal co d inju y (SCI) imp o es sensa ion, body con ol and o e all limb mo emen [14].
Mo eo e , ESCs-de i ed ca dio ascula p ogeni o cells egene a e ca diac issue, p o iding i s
mechanical epai [15,16]. ESCs-de i ed hepa ocy es ha e been success ully accomplished and hey
a e an impo an ool o d ug sc eening and cell he apy [17]. The ansplan a ion o ESCs-de i ed
chond ocy es e ec i ely heals knee join de ec s [18]. Al hough ESCs ha e eme ged as a p omising
ool in egene a i e medicine, hei use in esea ch has been highly deba ed due o e hical conce ns
[19]. TSPSCs, in opposi ion o ESCs, gi e ise o speci ic ypes o cells; mo eo e , hei numbe is
limi ed, making collec ion and in i o expansion ex emely di icul . When ac i a ed by a signal
deli e y, TSPSCs s a o p oli e a e and mig a e o he inju y si e, whe e hey di e en ia e and
acqui e a speci ic pheno ype con ibu ing o issue epai and enewal. In a clinic en i onmen , a
posi i e co ela ion be ween long- e m me abolic success upon ansplan a ion o panc ea ic
p ogeni o cells was demons a ed, p o ing ha despi e hei limi a ions, he cells ha e an
impo an egene a i e capaci y (induc ion o expandable issue-speci ic p ogeni o cells om
human). The MSCs ha e eme ged as a e sa ile and widely used he apeu ic ool in egene a i e
medicine. They a e ound in se e al in i o loca ions such as bone ma ow, skin, panc eas, hea ,
b ain, lung and o he s [20–22], and can be easily expanded wi hou losing hei mul ipo ency
capaci y. MSCs, when exposed o speci ic ac o s, can unde go a ilineage di e en ia ion:
os eogenesis, adipogenesis and chond ogenesis [23]; howe e , he di e en ia ion owa ds o he cell
ypes has also been epo ed in he li e a u e [24]. The umbilical co d blood p o ides an
immune-compa ible sou ce o s em cells ha is easily and sa ely collec ed and s o ed by UCB banks
[25]. Mo eo e , UCBSCs ha e also been conside ed as an al e na i e o ESCs due o hei con en in
mul ipo en s em cells, able o di e en ia e in se e al cell ypes [26]. Cu en ly, he egene a i e
capaci y o UCBSCs has been desc ibed o se e al diseases ha include neu onal inju y [27], ca diac
in a c ion [28] and bone egene a ion [29].
Fi s de eloped by Takahashi and Yamanaka in 2006, iPSCs can di e en ia e in o all cell ypes,
and hey can be ob ained om adul soma ic cells by he induc ion o he ou ansc ip ion ac o s
[30,31]. These cells ha e a high p oli e a i e capaci y and ha e been used o de i e skin cells [32,33],
epi helial s em cells [34] and ib oblas s [35], among o he s. Addi ionally, IPSCs ha e been
success ully gene a ed om ib oblas s, isola ed om pa ien s wi h ecessi e dys ophic bullosa,
which we e u he di e en ia ed in ke a inocy es o econs uc human skin s uc u e [36].
Figu e 1.
Depic ion o he cu en clinical/ he apeu ic app oaches o issue egene a ion: cell-based
he apies, implan a ion o syn he ic sca olds o epai and combina ion o a sca old wi h seeded cells.
Fi s de eloped by Takahashi and Yamanaka in 2006, iPSCs can di e en ia e in o all cell ypes,
and hey can be ob ained om adul soma ic cells by he induc ion o he ou ansc ip ion ac o s
[30,31]
.
These cells ha e a high p oli e a i e capaci y and ha e been used o de i e skin cells [
32
,
33
],
epi helial s em cells [
34
] and ib oblas s [
35
], among o he s. Addi ionally, IPSCs ha e been success ully
gene a ed om ib oblas s, isola ed om pa ien s wi h ecessi e dys ophic bullosa, which we e
u he di e en ia ed in ke a inocy es o econs uc human skin s uc u e [
36
]. Al hough he e a e
se e al p e-clinical e idences ha IPSCs may be a p omising he apeu ic app oach in egene a ion,
hei clinical applica ion has been delayed due o hei po en ial umo igenici y [37].
The na u al issues consis in cells and g ow h ac o s ha a e embedded in an ex acellula ma ix
(ECM). The ECM is a complex ib ous nanos uc u ed ma ix ha gi es bo h s uc u al and unc ional
suppo o cells. I con ols he mechanical and biological p ope ies o he issue, playing a key ole in
gene exp ession and cell dynamics (su i al, dea h p oli e a ion, di e en ia ion and mig a ion) [
38
].
Syn he ic o na u al sca olds ha e been s udied in egene a ion, hey ha e a h ee-dimensional (3D)
a chi ec u e and a e designed o eplica e he ECM mechanical and mic oen i onmen al p ope ies [
39
].
When associa ed wi h cells, he sca olds should be ailo ed o p o ide suppo , allowing he cells o
su i e, di e en ia e and mig a e, imp o ing he e icacy o cell ansplan a ion and egene a ion [
40
].
Biology 2021,9, 486 4 o 18
Mo eo e , hese ma e ials can be designed o unc ion as a ese oi , eleasing he he apeu ic
bioac i e molecules in a spa ially con olled manne [
41
]. One o he majo challenges ega ding cell
ansplan a ion in egene a i e medicine is hei long- e m su i al, gi en ha mos o he injec ed
cells die in a ew hou s ei he due o he lack o g ow h ac o s, insu icien suppo om he issue
(low ascula iza ion) o he ansplan a ion p ocedu e (mechanical s ess) [
42
]. The bioma e ials may
be ailo ed o add ess and o e come hese challenges, signi ican ly inc easing he cell su i al in
ansplan a ion. Ma e ial sca olds can modula e and con ol he s em cell a e by p o iding speci ic
en i onmen al condi ions (mechanical and biochemical) [
43
]. By changing he s i ness o se e al
ma e ials, MSCs inc eased he exp ession o ma ke s co esponding o os eogenic, myogenic and
neu ogenic lineages [
44
,
45
]. Mo eo e , he bioma e ial po osi y and adhesion p ope ies a e c ucial
o cell eng a men [
46
]. Nowadays, bioma e ials cons i u e an indispensable ool o egene a i e
medicine he apies, namely cell ansplan a ion, hey allow o imp o e cell su i al, enabling he issue
egene a ion and he clinical ansla ion o cell he apies. Cu en ly, 963 s udies, ei he comple ed
o in phases 3/4, use s em cells and add ess a wide a ay o diseases and pa hological condi ions
(wound healing, in e ili y, bone egene a ion, e c.). F om hose s udies, only 9 in ol e he use o a
sca old o a ma ix o suppo and deli e he cells, sugges ing ha he ield o bioma e ials s ill has a
pa h o a el be o e i s clinical eali y (www.clinical ial.go ).
2. Mi ochond ia miRNA Biology
Mic oRNAs (miRNAs) a e endogenous small, single-s anded molecules o noncoding RNA
(19–23 nucleo ides) ha ep esen a new le el o con ol o gene exp ession. miRNAs ac a he
pos - ansc ip ional le el o modula e p o ein-coding genes, ei he by blocking he ansla ion o
messenge RNA (mRNA) o by ac i ely encou aging i s deg ada ion, and i is well epo ed ha each
miRNA can a ge mul iple genes [
47
]. Gi en ha miRNAs a e now pos ula ed as mas e egula o s
and ine une s o gene exp ession, hese molecules migh enclose ele an diagnos ic, p ognos ic and
he apeu ic applica ions.
miRNAs a e cu en ly documen ed as ele an playe s in almos e e y biological p ocess,
om cell p oli e a ion o di e en ia ion, apop osis and o ganogenesis [
47
,
48
]. The inding and he
s udy o miRNAs has no iceably changed he classical unde s anding o gene exp ession and ou
comp ehension o he biogenesis and unc ion o miRNAs has ma kedly g own in ecen yea s.
Some associa ions be ween miRNA de egula ion and human disease ha e been epo ed in di e en
medical ields [
49
]. The esea ch in his new ‘a ena’ has exposed he eno mous po en ial o miRNAs
as ools o diagnos ics o he apeu ics. Mo e speci ically, se e al s udies ha e al eady explo ed he
modula ion o mi ochond ial DNA gene ics by miRNAs [
50
]. Mi ochond ia, besides chlo oplas s
in plan s, a e he only o ganelles ha possess a sepa a e genome, he so-called mi ochond ial DNA
(m DNA). Mu a ions in his DNA molecule ha e been shown o be in ol ed in an asso men
o bo h physiological (
e.g., hea p oduc ion
, eac i e oxygen species (ROS) p oduc ion, apop osis,
cellula di e en ia ion and aging) and pa hological ai s, including neu odegene a i e diseases,
diabe es, me abolic synd ome and cance s [
51
,
52
]. Addi ionally, he e is a ple ho a o c oss alk signals
ha allow he communica ion be ween he nuclea and mi ochond ial genomes. This mechanism o
egula ion is i al o he ac i i y o he whole cellula machine y, basically by modula ing mi ochond ial
biogenesis and me abolism [53] h ough ecip ocal mi ochond ial- o-nucleus communica ion [54,55].
The mos amous ole o mi ochond ia is o gene a e ATP h ough oxida i e phospho yla ion
ueled by a chain o ou p o ein complexes, he elec on anspo chain (ETC). An imp essi e numbe
o mo e han 1000 mi ochond ial p o eins ha e been disco e ed [
56
]. Mi ochond ial p o eins can
ha e a dis inc gene ic o igin. I is p edic ed ha ~99% o hese p o eins a e nuclea -encoded and
a e syn hesized in he cy oplasma ic compa men , being u he impo ed h ough mi ochond ial
memb ane anspo e s. The las ing 1% o mi ochond ial p o eins a e encoded by he mi ochond ial
genome and he mi ochond ial ibosome (mi o ibosome) is esponsible o he ansla ion o hese
mRNAs. Mo eo e , he mi ochond ion has i s own p o ein syn hesis machine y. As a esul ,
Biology 2021,9, 486 5 o 18
an app op ia e egula ion o mi ochond ial p o ein syn hesis is absolu ely equi ed o achie e and
main ain no mal mi ochond ial unc ion.
Rega ding miRNAs in mi ochond ia, i is well- ecognized nowadays ha se e al cellula
mechanisms in ol ing mi ochond ia a e egula ed by many gene ic playe s ha o igina e om
ei he nuclea - o mi ochond ial-encoded small noncoding RNAs (sncRNAs). G owing e idence
collec ed om whole genome and ansc ip ome sequencing highligh he ole o dis inc membe s o
his class, om sho in e e ing RNAs (siRNAs) o miRNAs and long noncoding RNAs (lncRNAs) [
57
].
Some o he mechanisms ha ha e been shown o be modula ed a e he exp ession o mi ochond ial
p o eins i sel , as well as he mo e complex coo dina ion o mi ochond ial s uc u e and dynamics wi h
i s unc ion [
58
–
60
]. The mechanisms in ol ed in mi ochond ial miRNAs anspo a e now being
inc easingly exposed and he e o e mo e and mo e ligh is being shed upon mi ochond ial miRNAs’
a ge s o de e mine hei ole in his unmapped cellula con ex [
57
,
61
]. Indeed, se e al s udies
ha e al eady disclosed he p esence o miRNAs in mi ochond ia [
59
]. Howe e , he mechanism
by which he nuclea -encoded miRNAs a e impo ed in o mi ochond ia is s ill no ully es ablished
(see Re e ence [
61
] o a ollow-up). On he o he hand, nume ous mi omiRs may be o igina ed s aigh
inside mi ochond ia, om mi ochond ial genome-de i ed mRNA. Undeniably, mi omiRs ypically ac
by egula ing gene exp ession inside mi ochond ia a he pos - ansc ip ional le el [
62
]. Fu he han
ha , some o he mi omiRs may also a ge nuclea -encoded mRNAs localized on he mi ochond ial
su ace [
57
]. Taken all oge he , hese disco e ies clea ly e eal he signi ican ole o mi omiRs
in egula ing mi ochond ial gene exp ession and mi ochond ial unc ions in bo h physiology and
pa hology [63], as summa ized in Figu e 2.
Biology 2020, 9, 486 5 o 19
mechanism o egula ion is i al o he ac i i y o he whole cellula machine y, basically by
modula ing mi ochond ial biogenesis and me abolism [53] h ough ecip ocal
mi ochond ial- o-nucleus communica ion [54,55].
The mos amous ole o mi ochond ia is o gene a e ATP h ough oxida i e phospho yla ion
ueled by a chain o ou p o ein complexes, he elec on anspo chain (ETC). An imp essi e
numbe o mo e han 1000 mi ochond ial p o eins ha e been disco e ed [56]. Mi ochond ial
p o eins can ha e a dis inc gene ic o igin. I is p edic ed ha ~99% o hese p o eins a e
nuclea -encoded and a e syn hesized in he cy oplasma ic compa men , being u he impo ed
h ough mi ochond ial memb ane anspo e s. The las ing 1% o mi ochond ial p o eins a e
encoded by he mi ochond ial genome and he mi ochond ial ibosome (mi o ibosome) is
esponsible o he ansla ion o hese mRNAs. Mo eo e , he mi ochond ion has i s own p o ein
syn hesis machine y. As a esul , an app op ia e egula ion o mi ochond ial p o ein syn hesis is
absolu ely equi ed o achie e and main ain no mal mi ochond ial unc ion.
Rega ding miRNAs in mi ochond ia, i is well- ecognized nowadays ha se e al cellula
mechanisms in ol ing mi ochond ia a e egula ed by many gene ic playe s ha o igina e om
ei he nuclea - o mi ochond ial-encoded small noncoding RNAs (sncRNAs). G owing e idence
collec ed om whole genome and ansc ip ome sequencing highligh he ole o dis inc membe s
o his class, om sho in e e ing RNAs (siRNAs) o miRNAs and long noncoding RNAs
(lncRNAs) [57]. Some o he mechanisms ha ha e been shown o be modula ed a e he exp ession
o mi ochond ial p o eins i sel , as well as he mo e complex coo dina ion o mi ochond ial s uc u e
and dynamics wi h i s unc ion [58–60]. The mechanisms in ol ed in mi ochond ial miRNAs
anspo a e now being inc easingly exposed and he e o e mo e and mo e ligh is being shed upon
mi ochond ial miRNAs’ a ge s o de e mine hei ole in his unmapped cellula con ex [57,61].
Indeed, se e al s udies ha e al eady disclosed he p esence o miRNAs in mi ochond ia [59].
Howe e , he mechanism by which he nuclea -encoded miRNAs a e impo ed in o mi ochond ia is
s ill no ully es ablished (see Re e ence [61] o a ollow-up). On he o he hand, nume ous
mi omiRs may be o igina ed s aigh inside mi ochond ia, om mi ochond ial genome-de i ed
mRNA. Undeniably, mi omiRs ypically ac by egula ing gene exp ession inside mi ochond ia a
he pos - ansc ip ional le el [62]. Fu he han ha , some o he mi omiRs may also a ge
nuclea -encoded mRNAs localized on he mi ochond ial su ace [57]. Taken all oge he , hese
disco e ies clea ly e eal he signi ican ole o mi omiRs in egula ing mi ochond ial gene
exp ession and mi ochond ial unc ions in bo h physiology and pa hology [63], as summa ized in
Figu e 2.
Figu e 2. Modula ion o physiologic and/o pa hologic mechanisms by mi ochond ial miRNAs.
Se e al mechanisms ha con ibu e o physiopa hology equi e some biological unc ions ha a e
modula ed by di e en mi ochond ial mic oRNAs.
Figu e 2.
Modula ion o physiologic and/o pa hologic mechanisms by mi ochond ial miRNAs.
Se e al mechanisms ha con ibu e o physiopa hology equi e some biological unc ions ha a e
modula ed by di e en mi ochond ial mic oRNAs.
3. Mi ochond ial miRNAs—Po en ial Con ibu ion o Regene a ion
Tissue epai and egene a ion depends on miRNA egula ion as hese small molecula silence s
play a undamen al pa in pos - ansc ip ional gene silencing. Mul iple key biological p ocesses
impo an o egene a ion such as cell g ow h and p oli e a ion, di e en ia ion and apop osis, as well as
mi ochond ial unc ion, a e igh ly con olled by hem [
64
,
65
]. Regula ion o miRNA exp ession le els
is c ucial as small changes in basal condi ions a e sequen ially p opaga ed and ampli ied h oughou
di e en biological pa hways, ul ima ely leading o changes in cell pheno ypes [
66
]. The e o e, a ple ho a
o aspec s in issue egene a ion could po en ially be con olled by he manipula ion o miRNAs.
Cu en ly, di e en e idence shows ha bo h nuclea -encoded miRNAs impo ed o mi ochond ia
and mi ochond ial genome-de i ed miRNA, bo h de ined as mi omiRs, may in luence mi ochond ial
dynamics, a undamen al p ocess o issue homeos asis (Table 1) [
67
,
68
]. In ac , egula ion o how

Biology 2021,9, 486 6 o 18
and how much ene gy cells equi e s ongly impac s s em cells’ a e, con olling he abili y o s em
cells o decide when o exi om hei quiescen s a e.
Some mi ochond ial miRNAs we e shown o modula e he di e en ia ion o muscle s em cell in o
unc ional muscle cells by egula ing mi ochond ia biogenesis (Table 1). By i sel , miR-1 exp ession
inc eases p o ein syn hesis, and ATP p oduc ion essen ial o op imal cell di e en ia ion [
69
]. Howe e ,
when miR-1 is simul aneously silenced wi h miR-133a in adul muscle s em cells
in i o
, he exp ession
o some mi ochond ial genes was educed, and a ypical mi ochond ia we e o med. Fu he mo e,
a pa allel
in i o
expe imen in a miR-1/133a double-knockou mouse model con i med comp omised
muscle pe o mance, as a consequence o mi ochond ial dys unc ion and impai ed me abolic
ma u a ion [
70
]. le -7b, which has a dual ole bo h on mi ochond ial dynamics as well as on di e en ia ion
and main enance o adul muscle cells [
71
], inhibi ed skele al muscle g ow h by blocking cell p oli e a ion
and p omo ed cell cycle a es and myo ib oblas p oli e a ion ia he IGF-2 signaling pa hway
in i o
[
72
]. miR-127 was shown o media e muscle s em cell di e en ia ion h ough di ec a ge ing
sphingosine-1-phospha e ecep o 3 (S1P3). Fo ced exp ession o miR-127 powe ed cell di e en ia ion
in o skele al cells bo h
in i o
and
in i o
. In a miR-127 ansgenic mouse su e ing Duchenne muscula
dys ophy, adminis a ion o his biomolecule induced skele al muscle egene a ion and imp o ed
muscula dys ophy h ough s em cell di e en ia ion [
73
]. O e exp ession o o he mi ochond ial
miRNAs, such as miR-125b and miR-128, was also co ela ed wi h inhibi ion o muscle s em cell
di e en ia ion and consequen ly impai ed muscle egene a ion [
74
]. O no e, miR-125b con ibu es
o his inhibi ion h ough insulin-like g ow h ac o 2 (IGF-2) a ge ing [
75
], while miR-128 supp esses
speci ici y p o ein-1 (Sp1) [
76
]. In con as , inhibi ion o miR-128 o e exp esses Sp1 p o ein le els,
abolishing p oli e a ion and inc easing di e en ia ion [
76
]. The di e en ial exp ession o mi omiRs
ha impac adul skele al muscle cell di e en ia ion and main enance a e depic ed in Figu e 3.
Biology 2020, 9, 486 6 o 19
3. Mi ochond ial miRNAs—Po en ial Con ibu ion o Regene a ion
Tissue epai and egene a ion depends on miRNA egula ion as hese small molecula
silence s play a undamen al pa in pos - ansc ip ional gene silencing. Mul iple key biological
p ocesses impo an o egene a ion such as cell g ow h and p oli e a ion, di e en ia ion and
apop osis, as well as mi ochond ial unc ion, a e igh ly con olled by hem [64,65]. Regula ion o
miRNA exp ession le els is c ucial as small changes in basal condi ions a e sequen ially p opaga ed
and ampli ied h oughou di e en biological pa hways, ul ima ely leading o changes in cell
pheno ypes [66]. The e o e, a ple ho a o aspec s in issue egene a ion could po en ially be
con olled by he manipula ion o miRNAs.
Cu en ly, di e en e idence shows ha bo h nuclea -encoded miRNAs impo ed o
mi ochond ia and mi ochond ial genome-de i ed miRNA, bo h de ined as mi omiRs, may in luence
mi ochond ial dynamics, a undamen al p ocess o issue homeos asis (Table 1) [67,68]. In ac ,
egula ion o how and how much ene gy cells equi e s ongly impac s s em cells’ a e, con olling
he abili y o s em cells o decide when o exi om hei quiescen s a e.
Some mi ochond ial miRNAs we e shown o modula e he di e en ia ion o muscle s em cell
in o unc ional muscle cells by egula ing mi ochond ia biogenesis (Table 1). By i sel , miR-1
exp ession inc eases p o ein syn hesis, and ATP p oduc ion essen ial o op imal cell di e en ia ion
[69]. Howe e , when miR-1 is simul aneously silenced wi h miR-133a in adul muscle s em cells in
i o, he exp ession o some mi ochond ial genes was educed, and a ypical mi ochond ia we e
o med. Fu he mo e, a pa allel in i o expe imen in a miR-1/133a double-knockou mouse model
con i med comp omised muscle pe o mance, as a consequence o mi ochond ial dys unc ion and
impai ed me abolic ma u a ion [70]. le -7b, which has a dual ole bo h on mi ochond ial dynamics as
well as on di e en ia ion and main enance o adul muscle cells [71], inhibi ed skele al muscle
g ow h by blocking cell p oli e a ion and p omo ed cell cycle a es and myo ib oblas p oli e a ion
ia he IGF-2 signaling pa hway in i o [72]. miR-127 was shown o media e muscle s em cell
di e en ia ion h ough di ec a ge ing sphingosine-1-phospha e ecep o 3 (S1P3). Fo ced
exp ession o miR-127 powe ed cell di e en ia ion in o skele al cells bo h in i o and in i o. In a
miR-127 ansgenic mouse su e ing Duchenne muscula dys ophy, adminis a ion o his
biomolecule induced skele al muscle egene a ion and imp o ed muscula dys ophy h ough s em
cell di e en ia ion [73]. O e exp ession o o he mi ochond ial miRNAs, such as miR-125b and
miR-128, was also co ela ed wi h inhibi ion o muscle s em cell di e en ia ion and consequen ly
impai ed muscle egene a ion [74]. O no e, miR-125b con ibu es o his inhibi ion h ough
insulin-like g ow h ac o 2 (IGF-2) a ge ing [75], while miR-128 supp esses speci ici y p o ein-1 (Sp1)
[76]. In con as , inhibi ion o miR-128 o e exp esses Sp1 p o ein le els, abolishing p oli e a ion and
inc easing di e en ia ion [76]. The di e en ial exp ession o mi omiRs ha impac adul skele al
muscle cell di e en ia ion and main enance a e depic ed in Figu e 3.
Figu e 3. Di e en ial exp ession o mi ochond ial miRNAs impac adul skele al muscle cell
di e en ia ion and main enance. By modula ing ene gy supply h ough mi ochond ia, hese
mi omiRs a e able o p omo e he ull di e en ia ion o muscle ibe s. Inc eased exp ession o he
Figu e 3.
Di e en ial exp ession o mi ochond ial miRNAs impac adul skele al muscle cell di e en ia ion
and main enance. By modula ing ene gy supply h ough mi ochond ia, hese mi omiRs a e able o
p omo e he ull di e en ia ion o muscle ibe s. Inc eased exp ession o he mi ochond ial gene is
needed o p omo e an adequa e mi ochond ial pe o mance and o allow mo e apid esponses o
physiological needs, namely issue egene a ion.
Tissue egene a ion a e inju y is a complex and a highly me abolically demanding p ocess [
77
].
Thus, egula ion o he mi ochond ial genome by mi omiRs may impac he exp ession o key
componen s d i ing ATP syn hesis, consequen ly in luencing egene a i e mechanisms (Table 1).
Mi ochond ial miR-181c, miR-1, miR-338 and miR-210 ha e been shown o a ge mul iple p o eins
ha modula e he mi ochond ial elec on anspo chain [
57
,
78
], as depic ed in Figu e 4. The impac o
miR-181c was demons a ed bo h
in i o
[
79
] and
in i o
[
80
] and mechanis ically desc ibed by binding
o 3’UTR mi ochond ial cy och ome c oxidase subuni (COX)-1, which a ec s he unc ion o mi ochond ial
elec on anspo chain complex IV. While o ced o e exp ession o miR-181c al e ed mi ochond ial
me abolism and ROS gene a ion, con ibu ing o hea ailu e, i s inhibi ion may be enough o balance
mi ochond ial bioene ge ics, po en ia ing ca diac emodeling o a leas con olling ca diac damages.
Biology 2021,9, 486 7 o 18
Recen ly, Bana a h e al. showed ha he loss o miR-181c, h ough MICU1 up egula ion, a speci ic
p omo e o Sp1, may p o ec he hea om inju y [
81
]. Mi ochond ial miR-338-5p in neu al cell cul u e
sys ems was demons a ed o modula e he exp ession o COX-IV and subuni s o he ATP syn hase
complex [
82
,
83
]. When an i-miR-338 was ans ec ed in o axons, he me abolic oxygen consump ion
was inc eased by abou 50% when compa ed wi h he non a ge ing cells, po en ia ing cell su i al.
Fu he mo e, miR-378 was shown o ha e an impo an ole in ca diac emodeling. This miRNA is
highly exp essed in diabe ic ca diac mi ochond ia and i educes ATP syn hase ac i i y by dec easing
mi ochond ial ATP6 exp ession. This e ec was u he es ed
in i o
by o e exp ession o mi omiR-378
in HL-1 cells [
84
]. Consis en ly,
in i o
deli e y o miR-378-3p an agomi p ese ed ATP6 p o ein
le els which balance he bioene ge ic de ici s, con ibu ing o an adequa e ca diac pump unc ion [
84
].
Biology 2020, 9, 486 7 o 19
mi ochond ial gene is needed o p omo e an adequa e mi ochond ial pe o mance and o allow mo e
apid esponses o physiological needs, namely issue egene a ion.
Tissue egene a ion a e inju y is a complex and a highly me abolically demanding p ocess
[77]. Thus, egula ion o he mi ochond ial genome by mi omiRs may impac he exp ession o key
componen s d i ing ATP syn hesis, consequen ly in luencing egene a i e mechanisms (Table 1).
Mi ochond ial miR-181c, miR-1, miR-338 and miR-210 ha e been shown o a ge mul iple p o eins
ha modula e he mi ochond ial elec on anspo chain [57,78], as depic ed in Figu e 4. The impac
o miR-181c was demons a ed bo h in i o [79] and in i o [80] and mechanis ically desc ibed by
binding o 3’UTR mi ochond ial cy och ome c oxidase subuni (COX)-1, which a ec s he unc ion o
mi ochond ial elec on anspo chain complex IV. While o ced o e exp ession o miR-181c al e ed
mi ochond ial me abolism and ROS gene a ion, con ibu ing o hea ailu e, i s inhibi ion may be
enough o balance mi ochond ial bioene ge ics, po en ia ing ca diac emodeling o a leas
con olling ca diac damages. Recen ly, Bana a h e al. showed ha he loss o miR-181c, h ough
MICU1 up egula ion, a speci ic p omo e o Sp1, may p o ec he hea om inju y [81].
Mi ochond ial miR-338-5p in neu al cell cul u e sys ems was demons a ed o modula e he
exp ession o COX-IV and subuni s o he ATP syn hase complex [82,83]. When an i-miR-338 was
ans ec ed in o axons, he me abolic oxygen consump ion was inc eased by abou 50% when
compa ed wi h he non a ge ing cells, po en ia ing cell su i al. Fu he mo e, miR-378 was shown
o ha e an impo an ole in ca diac emodeling. This miRNA is highly exp essed in diabe ic ca diac
mi ochond ia and i educes ATP syn hase ac i i y by dec easing mi ochond ial ATP6 exp ession.
This e ec was u he es ed in i o by o e exp ession o mi omiR-378 in HL-1 cells [84].
Consis en ly, in i o deli e y o miR-378-3p an agomi p ese ed ATP6 p o ein le els which
balance he bioene ge ic de ici s, con ibu ing o an adequa e ca diac pump unc ion [84].
Figu e 4. Mi ochond ial miRNAs modula e me abolic p ocesses. Mi ochond ial miRNAs ha e been
shown o egula e he mi ochond ial elec on anspo chain by a ge ing mul iple p o eins. By
impac ing mi ochond ial me abolism, ROS gene a ion and ATP p oduc ion, mi omiRs a e impo an
con ibu o s o issue egene a ion.
Ano he way o en ision issue egene a ion is by ecapi ula ing, o some ex en , he emb yonic
p og am ha ga e ise o he o iginal issue [85]. In his way, comp ehending cellula and molecula
mechanisms h oughou emb yonic de elopmen may help o pinpoin some impo an pa hways o
ecapi ula e in he egene a i e p ocess. As expec ed, mi omiRs ha e an impo an ole in
emb yogenesis. O no e, ea ly s ages o ca diogenesis a e p edominan ly suppo ed by miR-1 and
miR-133a, which sus ain he di e en ia ion o emb yonic s em cells and p ecu so s in o
ca diac-speci ic muscle lineage [86]. In ib oblas s and e al hea s, low o absen le els o miR-378
we e desc ibed, whe eas high le els o his molecule we e iden i ied in pos na al inju ed hea s [87].
miR-378, when o e exp essed in ca diomyocy es, enhanced apop osis by di ec a ge ing o IGF
Figu e 4.
Mi ochond ial miRNAs modula e me abolic p ocesses. Mi ochond ial miRNAs ha e
been shown o egula e he mi ochond ial elec on anspo chain by a ge ing mul iple p o eins.
By impac ing mi ochond ial me abolism, ROS gene a ion and ATP p oduc ion, mi omiRs a e impo an
con ibu o s o issue egene a ion.
Ano he way o en ision issue egene a ion is by ecapi ula ing, o some ex en , he emb yonic
p og am ha ga e ise o he o iginal issue [
85
]. In his way, comp ehending cellula and molecula
mechanisms h oughou emb yonic de elopmen may help o pinpoin some impo an pa hways o
ecapi ula e in he egene a i e p ocess. As expec ed, mi omiRs ha e an impo an ole in emb yogenesis.
O no e, ea ly s ages o ca diogenesis a e p edominan ly suppo ed by miR-1 and miR-133a, which sus ain
he di e en ia ion o emb yonic s em cells and p ecu so s in o ca diac-speci ic muscle lineage [
86
].
In ib oblas s and e al hea s, low o absen le els o miR-378 we e desc ibed, whe eas high le els
o his molecule we e iden i ied in pos na al inju ed hea s [
87
]. miR-378, when o e exp essed in
ca diomyocy es, enhanced apop osis by di ec a ge ing o IGF ecep o 1 and educed signaling in
he Ak cascade. Cu iously, inhibi ion o miR-378 p o ec ed ca diomyocy es agains ROS and hypoxia
eoxygena ion-induced cell dea h [
87
]. miR-378, al hough being nuclea -encoded, con ols mi ochond ial
me abolism as well as ene gy homeos asis [88].
Addi ionally, du ing human de elopmen , le els o miR-127-5p dec eased h oughou ime.
In e al issues like he li e and hea , hei me abolic ac i i y is mainly glycoly ic, which is hen
con e ed in oxida i e phospho yla ion. miR-127-5p was sugges ed o possibly pe o m an impo an
ole in con olling he bioene ge ic cell pa e n by a ge ing ATP5B. Consis en ly, he o e exp ession o
his molecule was able o dec ease he amoun o ATP5B p o ein by 50%
in i o
, ac i ely pa icipa ing
in he bioene ge ic changes [89].
Aging leads o inc eased cellula senescence and dec eases he unc ionali y o issue-speci ic s em
and p ogeni o cells which, in u n, is linked o a limi ed cellula egene a i e capaci y. Iden i ying which
molecula and cellula pa hways can po en ially decline he issue homeos asis and egene a i e
Biology 2021,9, 486 8 o 18
capaci y will p omo e he de elopmen o new he apeu ic app oaches. Elimina e senescen cells,
ebalance he ch onic oxida i e s ess and modula e impai ed signaling and p o ein quali y con ol
a e some examples ha may alle ia e issue de e io a ion and es o e he egene a i e capaci y [
90
].
Again, mi ochond ia do play a undamen al ole in he p e iously lis ed mechanisms since i s deple ion
inhibi ed cell senescence, while i p omo ed p oin lamma o y pheno ype and main ained glycolysis as
he cell bioene ge ic mode [
71
]. No ably, se e al mi omiRs ha e been associa ed o bo h senescence
and in lamma o y p ocesses by a ge ing he mi ochond ial genome. miR-146a-5p is one o hese
molecules ha by egula ing he unc ion o complex I and IV o he mi ochond ial elec on anspo
chain is able o con ol bo h in lamma ion and senescence [
71
]. Mi -146-5p has mi ochond ial-encoded
p o eins such as ND1, ND2, ND4, ND5, ND6 and ATP8 as pu a i e a ge s [
71
]. Since complex
I de e mines ROS p oduc ion in dys unc ional mi ochond ia, miR-146-5p is able o egula e his
p oduc ion ups eam, inducing cell senescen pheno ype. Al hough ROS a e impo an in physiological
p ocesses such as p oli e a ion and adap a ion o hypoxia, hei excess causes i e e sible damages [
91
].
The e o e, by inc easing ROS p oduc ion, miR-146a-5p sus ains a ch onic p oin lamma o y and
oxida i e s ess s a e by also a ge ing supe oxide dismu ase 2 (SOD2), an enzyme wi h an ioxidan
po en ial [
92
], and Bcl-2, a known p o ein ha egula es mi ochond ial dynamics, namely usion and
ission [
93
]. Addi ionally, oxida i e s ess induces pe meabili y ansi ion po e opening in mammalian
mi ochond ia, which u he con ibu es o i e e sible mi ochond ia damage and loss o unc ion [
94
].
Recen ly, miR-762 has also been disco e ed as a me abolic egula o . I s supp ession a enua ed he
dec ease in in acellula ATP le els, inc eased ROS p oduc ion and diminished mi ochond ial complex
I enzyme ac i i y. Speci ically, in ca diomyocy es and ischemia/ epe usion inju y, a ge ing miR-762
may be an in e es ing a enue o s udy o amelio a e myoca dial in a c ion damage [95].
Mi omiRs-19b, -20a, -17 and -106 a e he mos down egula ed miRNAs in se e al human senescen
cell and
in i o
aging models [
96
]. Speci ically, in endo helial cells, mi omiR-181a, -34a and -146a we e
shown o be o e exp essed in senescen cells when compa ed wi h young ones. Besides a ge ing
Bcl-2, hese miRNAs induce pe meabili y ansi ion po e opening and s imula e caspase-1 and 3 and
in e e e wi h apop osis suscep ibili y [97].
In u n, le -7b miRNA exp ession inc eases wi h aging. Hmga2 ansc ip ional egula o is a
known a ge o his miRNA whose exp ession is high in e al neu al s em cells. A s udy demons a ed
ha age was co ela ed wi h educed s em cell numbe s and sel - enewal h oughou he cen al
and pe iphe al ne ous sys ems in Hmga2-de icien mice. This e idence sugges s an impo an ole
o le -7b miRNA in he decline in neu al s em cell unc ion whose inhibi ion would po en ia e he
main enance o s emness [
98
]. Also, miR-181a exp ession ises du ing he senescen p ocess in human
de mal ib oblas , wi h i s o e exp ession being su icien o induce cell senescence [99].
As men ioned be o e, mi omiRs ha e been desc ibed as no el playe s in bo h physiologic and
pa hologic condi ions [
100
,
101
]. miR-1 is esponsible o p o ec ing hea s uc u e and unc ions agains
hype ophy, main aining ca dio ascula heal h. Thus, miR-1 is one o he c ucial egula o s o pa hological
ca diac hype ophy by ine- uning he ansla ion o di e en molecules, including euka yo ic ini ia ion
ac o 4E (EIF4E), Me 2a, Ga a4 and his one deace ylase 6 (HDAC6) [
102
,
103
]. MiR-1 also educes he
ca diac hype ophic esponse by nega i ely impac ing calmodulin in ol ed in calcium signaling [
104
]
ia di ec ly a ge ing hea -speci ic a binding p o ein 2 (FABP3). This p o ein in insically co ela es
wi h hea enla gemen and hype ophy in pa ien s. An opposi e ela ionship be ween he exp ession
o miR-1 in myoca dial issue and FABP3 le el in ci cula ion was obse ed [
105
]. O he au ho s ound
ha miR-1 supp esses ibulin-2 exp ession which, by consequence, s ops ac i a ion o TGF
β
signaling
and ex acellula ma ix emodeling in hype ophic hea [
106
,
107
]. In addi ion, miR-133, which is
amply exp essed in animal and human hea muscle issues, blocks hype hy oidism-induced ca diac
hype ophy by silencing he exp ession o ype 1 angio ensin II ecep o [
108
]. This molecule also
educes ca diac emodeling h ough a ge o Ak and i s downs eam signaling molecules, such as
Cdc42, Rho-A and Nel -A/WHSC2 [
109
]. miR-378 and miR-497 a e an ihype ophic biomolecules.
S udies demons a ed ha hey a e able o block IGF ecep o 1, g ow h ac o ecep o bound p o ein
Biology 2021,9, 486 9 o 18
2, kinase supp esso o Ras 1, Ras ac i i y, PI3K-Ak pa hway, Mapk1-MAPK signaling and he
Ra 1-MEK1-ERK1/2 pa hway [
110
], and in e e e wi h ansla ion o Si 4 [
111
]. Also, miR-212/132
amily [
112
] and miR-23a [
113
] a ge Foxo3 ansc ip ion ac o in ca diomyocy es, which alle ia es he
hype ophic clues, while miR-29a-3p hinde s ET-1-induced hype ophic esponse in ca diomyocy es
by di ec ly a ge ing 30UTR o NFATc4 [114].
In he same way, modula ing he magni ude o a ib o ic esponse would po en ia e egene a ion
by swi ching o cellula pa hways ha p og essi ely will d i e sca ing and degene a ion o he issue.
Likewise, se e al mi ochond ial miRNAs exe hei an i ib o ic ac i i y by modula ing he deposi ion
o componen s o ex acellula ma ix (Table 1) [
115
]. MiR-101, h ough a ge ing o TGF
β
RI and
c-Fos, dec eases ex acellula ma ix p o eins’ p oduc ion and p oli e a ion o ib oblas s. Induc ion o
miR-101 exp ession imp o es ca diac pe o mance decline caused by he ib o ic p ocess [
116
,
117
].
MiR-122 con ols TGF-
β
1 exp ession, an impo an ac o o se e e myoca dial ib osis ound o be
down egula ed in pa ien s [
118
]. By inhibi ing u in, miR-24 can supp ess di e en ia ion and mig a ion
o ca diac ib oblas s ia TGF
β
-smad2/3 signaling. Impo an ly,
in i o
, hea unc ion was pa ially
eco e ed by injec ing a syn he ic p ecu so o miR-24 [119].
miR-29a/b/c was shown o p omo e an an i- ib o ic e ec by di ec ly dec easing he p oduc ion
o ECM componen s in di e en issues such as hea , lung, kidney and li e . These miRNAs a ge
di e en collagens, such as FBN1, ELN1, MMP2 and ITGB1 genes [
120
–
123
]. Fo example, in a lung
ib osis
in i o
model d i en by silica, up egula ion o miR-29b p omo ed mesenchymal–epi helial
ansi ions (EMT) and supp essed gene exp ession o ex acellula ma ix- ela ed genes. Concomi an ly,
down egula ion o miR-29b imp o ed EMT by ele a ing he p o ein a io o E-cadhe in/ imen in and
up egula ed ECM- ela ed genes like imen in, alpha-smoo h muscle ac in, collagen ype 1 and Tg b1 [
124
].
miR-1224-5p exp ession showed simila e ec s in a lung ib osis model by a ge ing BECN1 [125].
In con as , miR-27a, ia he TGF-
β
1/Smad3 signaling pa hway, may con ibu e o ib osis in
s ep ozo ocin-induced diabe ic a s [
126
]. O e exp ession o his mi omiR ac i a es he TGF-
β
signaling pa hway, a key pa hway in ib osis pa hogenesis, inc easing he p oduc ion o connec i e
issue g ow h ac o , ib onec in and collagen I [
127
]. miR-21 also has a p o ib o ic ac i i y in lung,
hea and kidney. The p esence o his miRNA inc eases he p oduc ion o TGF-b by wo al e na i e
pa hways. In he canonical way, miR-21 a ge s Smad7 and supp esses Smad2/3 [
128
,
129
], o he wise,
miR-21 ac s ia Sp y1 on he ERK/MAPK pa hway [130].
Collec i ely, hese e idences sugges a possible ole o mi omiRs in issue egene a ion-associa ed
p ocesses. Ne e heless, u he s udies may be conduc ed o con i m he di ec ela ionship be ween
hese molecules and conc e e inju y scena ios.
Table 1. Summa y o mi omiRs unc ion and i s known a ge s.
miR Ta ge genes Func ion Re e ence
miR-1 ↑p o ein syn hesis
↑ATP p oduc ion [69]
EIF4E, Me 2a, Ga a4, HDAC6 Regula ion o ca diac hype ophy [102,103]
FABP3 Hea enla gemen and hype ophy [105]
Fibulin-2 ↓TGFβsignaling
↓ex acellula ma ix emodeling [106]
miR1/miR-133a
↑numbe o mi ochond ial genes
In luence on mi ochond ia mo phology
[70]
↑ca diac s em cell di e en ia ion [86]
Le -7b IGF-2
↓cell p oli e a ion
↑cell cycle a es
↑myo ib oblas p oli e a ion
[72]
Hmga2 ↑cell senescence [98]
miR-127 S1P3 ↑cell di e en ia ion [73]
ATP5B Con ol o bioene ge ic cell pa e n [89]
miR-125b IGF-2 ↓s em cell di e en ia ion [75]
miR-128 Sp1 ↓s em cell di e en ia ion [76]
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