Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage

• Main Authors: Gustafsson, Å.B (Author), Lally, N.S (Author), Liang, W. (Author), Moyzis, A.G (Author), Najor, R.H (Author)
• Format: Article
• Language: English
• Published: MDPI 2022
• Subjects: autophagy; Bnip3; heart; Mcl-1; mitochondria; mitophagy
• Online Access: View Fulltext in Publisher

 Myeloid cell leukemia-1 (Mcl-1) is a unique antiapoptotic Bcl-2 member that is critical for mitochondrial homeostasis. Recent studies have demonstrated that Mcl-1′ s functions extend beyond its traditional role in preventing apoptotic cell death. Specifically, data suggest that Mcl-1 plays a regulatory role in autophagy, an essential degradation pathway involved in recycling and eliminating dysfunctional organelles. Here, we investigated whether Mcl-1 regulates autophagy in the heart. We found that cardiac-specific overexpression of Mcl-1 had little effect on baseline autophagic activity but strongly suppressed starvation-induced autophagy. In contrast, Mcl-1 did not inhibit activation of autophagy during myocardial infarction or mitochondrial depolarization. Instead, overexpression of Mcl-1 increased the clearance of depolarized mitochondria by mitophagy independent of Parkin. The increase in mitophagy was partially mediated via Mcl-1′ s LC3-interacting regions and mutation of these sites significantly reduced Mcl-1-mediated mitochondrial clearance. We also found that Mcl-1 interacted with the mitophagy receptor Bnip3 and that the interaction was increased in response to mitochondrial stress. Overall, these findings suggest that Mcl-1 suppresses nonselective autophagy during nutrient limiting conditions, whereas it enhances selective autophagy of dysfunctional mitochondria by functioning as a mitophagy receptor. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.