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.
Highlights
These cells stably express a tandem mCherry-green fluorescent protein (GFP) tag attached to the outer mitochondrial membrane (OMM, via a localization signal derived from the protein FIS1)
We asked if HIF1α is required for mitophagy in response to carbonyl cyanide m-chlorophenyl hydrazone (CCCP) treatment, a depolarizing agent commonly used as an inducer of PINK1/Parkin-dependent mitophagy [20]
NIX-dependent mitophagy is dispensable for the initial stages of cardiomyoblast differentiation Our findings showed that NIX and BNIP3 were essential for HIF1α mediated mitophagy upon iron chelation in SH-SY5Y cells (Fig. 2)
Summary
The most characterised damage-induced mitophagy pathway, at least in terms of mechanism, involves activation of the Parkinson’srelated protein kinase PINK1 and ubiquitin E3 ligase Parkin. As mitochondria are solely responsible for oxygen-dependent energy production, it is reasonable to assume that mitophagy is under metabolic control This appears to be the case, with PINK1/Parkin-dependent mitophagy being overridden in conditions that force oxidative phosphorylation (OXPHOS) over glycolysis [7, 8]. We previously identified that loss of cellular iron generates a robust PINK1/Parkin-independent mitophagy response [10] This distinct mitophagy pathway was under metabolic control: as with the PINK1/Parkin pathway, growth of cells in galactose medium to bypass glycolysis and stimulate OXPHOS, abolished mitophagy [10].
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