BNIP3L/NIX and FUNDC1-mediated mitophagy is required for mitochondrial network remodeling during cardiac progenitor cell differentiation

Abstract

Cell based therapies represent a very promising strategy to repair and regenerate the injured heart to prevent progression to heart failure. To date, cell based therapies have had limited success due to a lack of survival and retention of the infused cells. Therefore, it is important to increase our understanding of the biology of these cells and utilize this information to enhance their survival and function in the unfavorable environment of the injured heart. Mitochondria are critical for progenitor cell function and survival. Here we demonstrate the importance of mitochondrial autophagy, or mitophagy, in the differentiation process in adult cardiac progenitor cells (CPCs). We found that mitophagy is rapidly induced upon initiation of differentiation in CPCs. We also found that mitophagy was mediated by the mitophagy receptors pathway, rather than the PINK1/Parkin pathway. Mitophagy receptors Nix and Fundc1, but not Bnip3, were upregulated during differentiation. Mitophagy mediated by Nix and Fundc1 was not involved in regulating progenitor cell fate determination, mitochondrial biogenesis, or reprogramming. Instead, mitophagy facilitated the CPCs to undergo proper mitochondrial network reorganization during differentiation. Abrogating Nix/Fundc1‐mediated mitophagy during differentiation led to mitochondrial fragmentation and failure to form an interconnected mitochondrial network. It also led to increased susceptibility to hydrogen peroxide mediated cell death during differentiation. Finally, aging is associated with accumulation of mtDNA mutations in cells and we found that acquiring mtDNA mutations selectively disrupted the differentiation‐activated mitophagy program in CPCs. These findings demonstrate the importance of Nix/Fundc1‐mediated mitophagy as a critical regulator of mitochondrial network formation in differentiating progenitor cells, as well as the consequences of accumulating mtDNA mutations. Support or Funding Information A.B. Gustafsson is supported by an AHA Established Investigator Award, and by NIH R21AG052280, R01HL087023, R01HL132300 and P01HL085577. M.A. Lampert is supported by the UCSD Graduate Training Program in Cellular and Molecular Pharmacology grant T32GM007752. A.M. Orogo is supported in part by the UCSD Graduate Training Program in Cellular and Molecular Pharmacology through an institutional training grant from the National Institute of General Medical Sciences T32GM007752, and National Institutes of Health NRSA Predoctoral Fellowship F31HL123309. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Mitophagy: An Emerging Role in Aging and Age-Associated Diseases

“…Interestingly, mtDNA released from damaged mitochondria triggers inflammatory responses in cardiomyocytes that culminate in myocarditis and dilated cardiomyopathy (Oka et al, 2012). Moreover, Parkin mediated mitophagy turns over fetal cardiomyocyte mitochondria to facilitate the replacement of mature adult mitochondria, an effect that likely contributes to the perinatal maturation of cardiac metabolism (Kageyama et al, 2014;Gong et al, 2015;Lampert et al, 2019).…”

“…FUNDC1 and BCL2 interacting protein 3 like (BNIP3L, better known as NIX) but not PINK1/Parkin-dependent mitophagy facilitates the removal of impaired mitochondria and thus maintains mitochondrial network reorganization during cardiac progenitor cell (CPC) differentiation. Interestingly, mice expressing a proofreading-defective mitochondrial DNA polymerase G gamma (PolG D257A/D257A ), experience premature aging and develop accelerated age-related cardiomyopathy due to the accumulation of mtDNA mutations (Lampert et al, 2019).…”

Mammalian Mitophagosome Formation: A Focus on the Early Signals and Steps

“…FUNDC1 has also been reported to be regulated by direct phosphorylation by ULK1 (at serine 17) to promote mitophagy both in the context of hypoxia and of FCCP treatment . Recently, NIX and FUNDC1 have been reported to be essential for mitophagy during cardiac progenitor cell differentiation, mediating mitochondrial network remodeling (Lampert et al, 2019). Bcl2-L-13 has been suggested to be the mammalian homolog of the yeast Atg32 due to sequence similarity and because it can rescue mitophagy in yeast upon loss of Atg32 (Murakawa et al, 2015).…”

Prohibitin 2 deficiency impairs cardiac fatty acid oxidation and causes heart failure

“…It is a complex clinical syndrome, in which abnormality in cardiac pump function leads to inadequate oxygen supply and perturbed energy metabolism for maintaining normal requirement of cardiac contractility 2 . A variety of mechanisms have been involved in the pathogenesis of heart failure, including metabolic disorder, mitochondrial dysfunction, autophagy, apoptosis, and genetic or epigenetic dysregulation [3][4][5] . Better understanding the underlying mechanisms of heart failure will provide potential therapeutic targets.…”