The Role of Alternative Mitophagy in Heart Disease

Abstract

Autophagy is essential for maintaining cellular homeostasis through bulk degradation of subcellular constituents, including misfolded proteins and dysfunctional organelles. It is generally governed by the proteins Atg5 and Atg7, which are critical regulators of the conventional autophagy pathway. However, recent studies have identified an alternative Atg5/Atg7-independent pathway, i.e., Ulk1- and Rab9-mediated alternative autophagy. More intensive studies have identified its essential role in stress-induced mitochondrial autophagy, also known as mitophagy. Alternative mitophagy plays pathophysiological roles in heart diseases such as myocardial ischemia and pressure overload. Here, this review discusses the established and emerging mechanisms of alternative autophagy/mitophagy that can be applied in therapeutic interventions for heart disorders.

Keywords: Rab9; alternative autophagy; conventional autophagy; heart disease; mitophagy.

Figure 1

Brief molecular mechanisms of conventional and alternative autophagy. (A) Conventional autophagy is initiated by Ulk1/2, Beclin1 complex, and Atg5/7-dependent LC3 lipidation. (B) Alternative autophagy is initiated by Ulk1, Beclin1 complex, and Rab9-dependent autophagosome generation.

Figure 2

Receptors and adaptors of mitophagy. (A) Mitophagy adaptors have both LIR and UBD that interact with ubiquitin and LC3, respectively, in response to mitophagy activation. (B) Several mitophagy receptors facilitate mitophagy in response to various stress conditions.

Figure 3

Molecular mechanism of Ulk1/Rab9-dependent alternative mitophagy. Upon mitophagy activation signaling, activated Ulk1 phosphorylates Rab9 at Ser179, thereby recruiting Rip1 and Drp1 to promote alternative mitophagy.

Figure 4

Schematic model of mitophagy in response to heart disease. (A) Mice exhibited increased alternative mitophagy levels 30 min after ischemia or 48 h after starvation, whereas conventional mitophagy did not change in response to energy stress. (B) Mice fed a high-fat diet (HFD) exhibited increased conventional mitophagy up to 6 w after the beginning of HFD feeding. The level of alternative mitophagy kept increasing even after 24 weeks of HFD feeding. (C). During pressure overload, conventional mitophagy was acutely activated within a day of TAC, whereas alternative mitophagy exhibited prolonged activation between 3 and 7 days after TAC.