A time to reap, a time to sow: mitophagy and biogenesis in cardiac pathophysiology

Abstract

Balancing mitophagy and mitochondrial biogenesis is essential for maintaining a healthy population of mitochondria and cellular homeostasis. Coordinated interplay between these two forces that govern mitochondrial turnover plays an important role as an adaptive response against various cellular stresses that can compromise cell survival. Failure to maintain the critical balance between mitophagy and mitochondrial biogenesis or homeostatic turnover of mitochondria results in a population of dysfunctional mitochondria that contribute to various disease processes. In this review we outline the mechanics and relationships between mitophagy and mitochondrial biogenesis, and discuss the implications of a disrupted balance between these two forces, with an emphasis on cardiac physiology. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease".

Keywords: Autophagy; Cardiac; Mitochondria; Mitochondrial biogenesis; Mitophagy; Pathogenesis.

Figure 1. Parkin-dependent Mitochondrial Autophagy (Mitophagy)

1. Cellular stress, such as ischemia/reperfusion, triggers fragmentation of the mitochondria mediated by Drp1, segregating low-membrane potential mitochondria from the rest of the network. Ischemia/reperfusion injury also leads to the collapse of mitochondrial membrane potential which deactivates PARL and MPP, allowing for PINK1 stabilization on the OMM.

2. Parkin is recruited to the OMM where it binds Mfn2 and ubiquitinates multiple OMM proteins, marking them for proteasomal degradation and targeted recognition of the ubiquitin-decorated mitochondrion.

3. Autophagy adapter proteins such as p62 are then recruited to the mitochondria which in turn bind the ubiquitinated mitochondrion to the phagophore through interaction with LC3 or homologs.

4. Once the autophagosome has fully engulfed the mitochondrion, it fuses with a lysosome to form the autophagolysosome where final degradation of bulk contents is completed.

5. Shaded area indicates atypical players that participate in recognition and targeting of mitochondria for autophagic clearance. These include Nix and Bnip3 which bind LC3 or homologs including GABARAPL1.

Figure 2. PGC-1α Regulation of Mitochondrial Biogenesis

PGC-1α is considered a master regulator of mitochondrial biogenesis. Transcriptional control of PGC-1α expression is closely linked to environmental cues of fuel availability, fuel type, and cellular energy requirements. PGC-1α transcription is governed by multiple transcription factors (trans) including PPAR/RXR, MEF2, C/EBP, FoxO, CREB/CRTC, ERRγ, and MyoD/E2A. These factors in turn are activated by specific signal pathways including free fatty acids, AMPK, calcineurin, p38 MAPK, CaMK IV, and PKA, and suppressed by other signals including GCN5, AKT and SHP. In addition to transcriptional control, PGC-1α activity is regulated by acetylation and phosphorylation by the factors illustrated here. Ultimately, PGC-1α increases mitochondrial biogenesis and the capacity to perform OXPHOS, in particular, fatty acid oxidation.

Figure 3. The Parkin-PARIS Axis Coordinates Mitophagy with Mitochondrial Biogenesis

Basal state cellular homeostasis is characterized by balanced mitophagy and mitochondrial biogenesis (mitochondrial turnover). This maintains a network of healthy mitochondria. Mitophagy is linked to a transcriptional program for mitochondrial biogenesis. One pathway in this tightly coordinated process involves Parkin and PARIS. Triggers of mitophagy increase Parkin expression and activity, leading to proteasomal degradation of PARIS. Diminished PARIS levels relieve the transcriptional repression of PGC-1α, priming mitochondrial biogenesis.

Figure 4. Cardiac Mitophagy Regulation and Significance

Mitophagy is essential during cardiomyocyte differentiation and for homeostatic mitochondrial turnover to maintain a healthy population of mitochondria. During cardiac stress such as ischemia/reperfusion, mitophagy functions to eliminate damaged mitochondria and reduce injury. Mitophagy is also critical for ischemic preconditioning. Circadian rhythm regulates basal levels of cardiac mitophagy. Nutrient overload, type 2 diabetes, obesity, and advanced age may compromise cardiac autophagy and mitophagy, disrupting this adaptive physiological response to stress.