Mitophagy programs: mechanisms and physiological implications of mitochondrial targeting by autophagy

Abstract

Mitochondria are an essential source of ATP for cellular function, but when damaged, mitochondria generate a plethora of stress signals, which lead to cellular dysfunction and eventually programmed cell death. Thus, a major component of maintaining cellular homeostasis is the recognition and removal of dysfunctional mitochondria through autophagy-mediated degradation, i.e., mitophagy. Mitophagy further constitutes a developmental program, and undergoes a high degree of crosstalk with apoptosis. Reduced mitochondrial quality control is linked to disease pathogenesis, suggesting the importance of process elucidation as a clinical target. Recent work has revealed multiple mitophagy programs that operate independently or undergo crosstalk, and require modulated autophagy receptor activities at outer membranes of mitochondria. Here, we review these mitophagy programs, focusing on pathway mechanisms which recognize and target mitochondria for sequestration by autophagosomes, as well as mechanisms controlling pathway activities. Furthermore, we provide an introduction to the currently available methods for detecting mitophagy.

Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations

“…The pathogenesis of PD, however, involves abnormalities in mitochondrial function, which include impaired mitochondrial electron transport chain function, damaged mitochondrial DNA, impaired calcium buffering, and abnormal mitochondrial morphology and dynamics [4–7]. Moreover, familial PD can be caused by mutations in genes that encode the proteins PINK (PTEN induced putative kinase 1), PRKN/PARK2 (parkin RBR E3 ubiquitin protein ligase) and PARK7/DJ-1 [8], each of which contribute to the selective removal of dysfunctional mitochondria by macroautophagy (autophagy hereafter). In this process, known as mitophagy, compromised mitochondria are flagged by autophagy receptors, recognized and engulfed by phagophores, which mature into autophagosomes, and delivered to lysosomes for degradation.…”

Contribution of Mitophagy to Cell‐Mediated Mineralization: Revisiting a 50‐Year‐Old Conundrum

“…Mitophagy is a specific form of autophagy through which damaged or effete mitochondria are delivered to the lysosomes for hydrolytic and enzymatic degradation 9. Similar to autophagy, sequestration of mitochondria involves participation of autophagosomes or direct involvement of lysosomal membranes 9, 10.…”

Mitochondrial autophagy promotes healthy aging

“…Mitophagy is a dedicated form of autophagy that selectively removes damaged or old mitochondria, which has been identified from yeast to mammals as an important mitochondrial quality control pathway. 3 Of note, we recently reported for the first time that in C. elegans partial suppression of mitochondrial electron transport chain regulatory proteins (e.g. frataxin) extends lifespan through the activation of a pdr-1/ Parkin-, pink-1/ Pink-, and dct-1/ Bnip3-dependent mitophagy, which is promoted by the induction of a moderate iron starvation response (Fig.…”

“…4 Several studies have shown that mitophagy defects are implicated in a wide array of human disorders including neurodegenerative diseases, myopathies and cancer. 3 Tumor development can result from alteration of basic cellular functions such as metabolism, differentiation, proliferation and death programs. In recent years, it has been accepted that autophagy, in addition to its cell survival function, can elicit cell growth inhibition and cell death functions thus playing a Janus faced role in promoting tumor cell survival or tumor regression respectively.…”

“…6 Consistent with mitophagy as a possible tumor suppressor mechanism, reduced expression of BNIP3, a mitophagy specific regulator, was found in different type of cancers. 3 Therefore developing novel approaches to activate mitophagy may lead to new strategies to prevent tumor formation or induce tumor regression.…”