PMID- 35108116
OWN - NLM
STAT- MEDLINE
DCOM- 20220503
LR  - 20230302
IS  - 1522-1563 (Electronic)
IS  - 0363-6143 (Print)
IS  - 0363-6143 (Linking)
VI  - 322
IP  - 3
DP  - 2022 Mar 1
TI  - Manipulation of the miR-378a/mt-ATP6 regulatory axis rescues ATP synthase in the 
      diabetic heart and offers a novel role for lncRNA Kcnq1ot1.
PG  - C482-C495
LID - 10.1152/ajpcell.00446.2021 [doi]
AB  - Diabetes mellitus has been linked to an increase in mitochondrial microRNA-378a 
      (miR-378a) content. Enhanced miR-378a content has been associated with a 
      reduction in mitochondrial genome-encoded mt-ATP6 abundance, supporting the 
      hypothesis that miR-378a inhibition may be a therapeutic option for maintaining 
      ATP synthase functionality during diabetes mellitus. Evidence also suggests that 
      long noncoding RNAs (lncRNAs), including lncRNA potassium voltage-gated channel 
      subfamily Q member 1 overlapping transcript 1 (Kcnq1ot1), participate in 
      regulatory axes with microRNAs (miRs). Prediction analyses indicate that Kcnq1ot1 
      has the potential to bind miR-378a. This study aimed to determine if loss of 
      miR-378a in a genetic mouse model could ameliorate cardiac dysfunction in type 2 
      diabetes mellitus (T2DM) and to ascertain whether Kcnq1ot1 interacts with 
      miR-378a to impact ATP synthase functionality by preserving mt-ATP6 levels. 
      MiR-378a was significantly higher in patients with T2DM and 25-wk-old Db/Db mouse 
      mitochondria, whereas mt-ATP6 and Kcnq1ot1 levels were significantly reduced when 
      compared with controls. Twenty-five-week-old miR-378a knockout Db/Db mice 
      displayed preserved mt-ATP6 and ATP synthase protein content, ATP synthase 
      activity, and preserved cardiac function, implicating miR-378a as a potential 
      therapeutic target in T2DM. Assessments following overexpression of the 500-bp 
      Kcnq1ot1 fragment in established mouse cardiomyocyte cell line (HL-1) 
      cardiomyocytes overexpressing miR-378a revealed that Kcnq1ot1 may bind and 
      significantly reduce miR-378a levels, and rescue mt-ATP6 and ATP synthase protein 
      content. Together, these data suggest that Kcnq1ot1 and miR-378a may act as 
      constituents in an axis that regulates mt-ATP6 content, and that manipulation of 
      this axis may provide benefit to ATP synthase functionality in type 2 diabetic 
      heart.
FAU - Durr, Andrya J
AU  - Durr AJ
AD  - Division of Exercise Physiology, West Virginia University School of Medicine, 
      Morgantown, West Virginia.
AD  - Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University 
      School of Medicine, Morgantown, West Virginia.
FAU - Hathaway, Quincy A
AU  - Hathaway QA
AUID- ORCID: 0000-0001-8226-2319
AD  - Division of Exercise Physiology, West Virginia University School of Medicine, 
      Morgantown, West Virginia.
AD  - Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University 
      School of Medicine, Morgantown, West Virginia.
AD  - Center for Inhalation Toxicology, West Virginia University School of Medicine, 
      Morgantown, West Virginia.
FAU - Kunovac, Amina
AU  - Kunovac A
AUID- ORCID: 0000-0002-5107-3993
AD  - Division of Exercise Physiology, West Virginia University School of Medicine, 
      Morgantown, West Virginia.
AD  - Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University 
      School of Medicine, Morgantown, West Virginia.
AD  - Center for Inhalation Toxicology, West Virginia University School of Medicine, 
      Morgantown, West Virginia.
FAU - Taylor, Andrew D
AU  - Taylor AD
AD  - Division of Exercise Physiology, West Virginia University School of Medicine, 
      Morgantown, West Virginia.
AD  - Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University 
      School of Medicine, Morgantown, West Virginia.
FAU - Pinti, Mark V
AU  - Pinti MV
AD  - Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University 
      School of Medicine, Morgantown, West Virginia.
AD  - West Virginia University School of Pharmacy, Morgantown, West Virginia.
AD  - Department of Physiology and Pharmacology, West Virginia University School of 
      Medicine, Morgantown, West Virginia.
FAU - Rizwan, Saira
AU  - Rizwan S
AD  - Division of Exercise Physiology, West Virginia University School of Medicine, 
      Morgantown, West Virginia.
AD  - Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University 
      School of Medicine, Morgantown, West Virginia.
FAU - Shepherd, Danielle L
AU  - Shepherd DL
AD  - Division of Exercise Physiology, West Virginia University School of Medicine, 
      Morgantown, West Virginia.
FAU - Cook, Chris C
AU  - Cook CC
AD  - Cardiovascular and Thoracic Surgery, West Virginia University School of Medicine, 
      Morgantown, West Virginia.
FAU - Fink, Garrett K
AU  - Fink GK
AD  - Division of Exercise Physiology, West Virginia University School of Medicine, 
      Morgantown, West Virginia.
FAU - Hollander, John M
AU  - Hollander JM
AUID- ORCID: 0000-0001-5724-694X
AD  - Division of Exercise Physiology, West Virginia University School of Medicine, 
      Morgantown, West Virginia.
AD  - Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University 
      School of Medicine, Morgantown, West Virginia.
AD  - Center for Inhalation Toxicology, West Virginia University School of Medicine, 
      Morgantown, West Virginia.
LA  - eng
GR  - R01 HL128485/HL/NHLBI NIH HHS/United States
GR  - R56 HL128485/HL/NHLBI NIH HHS/United States
GR  - HL128485/HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/
GR  - U54 GM104942/GM/NIGMS NIH HHS/United States
GR  - P20 GM103434/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20220202
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (MT-ATP6 protein, human)
RN  - 0 (MicroRNAs)
RN  - 0 (RNA, Long Noncoding)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 3.6.3.- (Mitochondrial Proton-Translocating ATPases)
SB  - IM
MH  - Adenosine Triphosphate
MH  - Animals
MH  - *Diabetes Mellitus, Type 2/genetics
MH  - Humans
MH  - Mice
MH  - *MicroRNAs/genetics/metabolism
MH  - Mitochondrial Proton-Translocating ATPases/genetics/metabolism
MH  - Myocytes, Cardiac/metabolism
MH  - *RNA, Long Noncoding/genetics
PMC - PMC8917913
OTO - NOTNLM
OT  - heart
OT  - lncRNA
OT  - microRNA
OT  - mitochondria
OT  - type 2 diabetes mellitus
COIS- No conflicts of interest, financial or otherwise, are declared by the authors.
EDAT- 2022/02/03 06:00
MHDA- 2022/05/04 06:00
PMCR- 2023/03/01
CRDT- 2022/02/02 17:14
PHST- 2022/02/03 06:00 [pubmed]
PHST- 2022/05/04 06:00 [medline]
PHST- 2022/02/02 17:14 [entrez]
PHST- 2023/03/01 00:00 [pmc-release]
AID - C-00446-2021 [pii]
AID - 10.1152/ajpcell.00446.2021 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2022 Mar 1;322(3):C482-C495. doi: 
      10.1152/ajpcell.00446.2021. Epub 2022 Feb 2.