HIF1α-dependent mitophagy facilitates cardiomyoblast differentiation

Authors:

Jin-Feng Zhao1,#, Catherine E. Rodger1,#, George F. G. Allen1, Simone Weidlich1 and Ian G. Ganley1
PDF Download PubMed Link Supplemental Information
Affiliations:

1 MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.

# Equal contribution.

Keywords: 

mitophagy, HIF1α, NIX, BNIP3, iron chelation, cardiomyocyte, differentiation.

Abbreviations:

Baf A1 – bafilomycin A1;

CCCP - carbonyl cyanide m-chlorophenyl hydrazine;

DFP – deferiprone;

GFP – green fluorescent protein;

KO – knock out;

MHC – myosin heavy chain;

mTOR – mammalian target of rapamycin;

NT – non-targeting;

OCR – oxygen consumption rate;

OMM – outer mitochondrial membrane;

OXPHOS – oxidative phosphory-lation;

siRNA – small interfering RNA;

WT – wild type.

Corresponding Author(s):

Ian G. Ganley, MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK; i.ganley@dundee.ac.uk

Conflict of interest statement:

The authors declare they have no conflict of interest.

Please cite this article as:

Jin-Feng Zhao, Catherine E. Rodger, George F. G. Allen, Simone Weidlich and Ian G. Ganley (2020). HIF1α-dependent mitophagy facilitates cardiomyoblast differentiation. Cell Stress 4(5): 99-113. doi: 10.15698/cst2020.05.220

© 2020 Zhao et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.

Abstract:

Mitophagy is thought to play a key role in eliminating damaged mitochondria, with diseases such as cancer and neurodegeneration exhibiting defects in this process. Mitophagy is also involved in cell differentiation and maturation, potentially through modulating mitochondrial metabolic reprogramming. Here we examined mitophagy that is induced upon iron chelation and found that the transcriptional activity of HIF1α, in part through upregulation of BNIP3 and NIX, is an essential mediator of this pathway in SH-SY5Y cells. In contrast, HIF1α is dispensable for mitophagy occurring upon mitochondrial depolarisation. To examine the role of this pathway in a metabolic reprogramming and differentiation context, we utilised the H9c2 cell line model of cardiomyocyte maturation. During differentiation of these cardiomyoblasts, mitophagy increased and required HIF1α-dependent upregulation of NIX. Though HIF1α was essential for expression of key cardiomyocyte markers, mitophagy was not directly required. However, enhancing mitophagy through NIX overexpression, accelerated marker gene expression. Taken together, our findings provide a molecular link between mitophagy signalling and cardiomyocyte differentiation and suggest that although mitophagy may not be essential per se, it plays a critical role in maintaining mitochondrial integrity during this energy demanding process.