Mitophagy and Disease: New Avenues for Pharmacological Intervention

Abstract

The process of intracellular macromolecular degradation known as macroautophagy has long been associated with the degradation of mitochondria. Recent studies have provided evidence that the process of mitochondria degradation via autophagy, now referred to as mitophagy, appears to be specifically targeted to mitochondria and highly regulated under both physiologic and pathologic conditions. This article provides a review of key developments in mitophagy research, including background information on the history, mechanisms, and regulation of macroautophagy, as well as discoveries that have enhanced our understanding of the specificity and independent regulation of mitophagy. This is followed by an analysis of how our current understanding of the mechanics and regulation of mitophagy may be exploited to yield pharmacological interventions for mitochondria-associated diseases. As yet, the potential for mitophagy-related pharmacological treatments for disease remains largely untapped. However, rapid progress in our understanding of both mitophagy and the pathology of mitochondria-related diseases is leading us towards the convergence of science and medicine which will inevitably result in new and potent pharmacological therapies for the treatment of these maladies.

Autophagy and genomic integrity

“…115,116 In this sense, induction of autophagy has given promising results in mouse models of Alzheimer's disease 117 and other neurodegenerative diseases. 118 Further, the increased genomic instability observed in parkin-deleted cells could also be explained by the observation that parkin translocates from the cytosol to the nucleus where it participates in DDR after DNA damage. 115,116 Therefore, the parkin protein is an important factor in both DDR and autophagic removal of injured mitochondria.…”

Phosphorylation Events in Selective Mitophagy: Possible Biochemical Markers?

“…Similar to the proposed dual roles of autophagy in cancers, mitophagy could be a double-edged sword in the development of cancer [16,109]. During the early stage of cancer development, mitophagy functions to effectively remove damaged mitochondria to maintain the well-being of the cells and to prevent the occurrence of cancers [16].…”

“…However, phosphorylation of these sites is not required for Atg32-Atg8 interaction [65]. Likewise, phosphorylation of Ser-17 and Ser-24 of Bnip3 also promotes its binding to LC3-B and GATE- 16 What are the kinases and phosphatases that mediate this reversible phosphorylation? A recent report using kinase screening showed that casein kinase 2 (CK2) phosphorylates the OMM protein Atg32 at Ser-114 and Ser-119 in vitro to promote its interaction with the cytosolic adaptor protein Atg11 in yeast, thus resulting in recruitment into vacuoles and mitophagy [67 •• ] Furthermore, CK2 inhibition selectively prevents Atg32-Atg11 interaction-dependent mitophagy without affecting the Cvt pathway, pexophagy and macroautophagy [67 •• ].…”

“…During the early stage of cancer development, mitophagy functions to effectively remove damaged mitochondria to maintain the well-being of the cells and to prevent the occurrence of cancers [16]. During the late stage of cancer development, the hypoxic conditions inside the tumor will activate mitophagy, which can digest unwanted mitochondria to sustain the survival of the cancer [114,115].…”

“…To fulfill such diverse or even opposing functions, mitochondrial quality must be tightly monitored to avoid harmful effects from mitochondria and to maintain the health of the cell [10][11][12][13][14]. The accumulation of dysfunctional mitochondria is the characteristic of different types of diseases, including heart failure, Alzheimer's disease, Parkinson's disease and cancers [15][16][17][18]. One of the reasons could be defective mitochondrial quality control.…”