Elsevier

Pharmacology & Therapeutics

Volume 178, October 2017, Pages 157-174
Pharmacology & Therapeutics

Mitophagy and age-related pathologies: Development of new therapeutics by targeting mitochondrial turnover

https://doi.org/10.1016/j.pharmthera.2017.04.005Get rights and content

Abstract

Mitochondria are highly dynamic and semi-autonomous organelles, essential for many fundamental cellular processes, including energy production, metabolite synthesis, ion homeostasis, lipid metabolism and initiation of apoptotic cell death. Proper mitochondrial physiology is a prerequisite for health and survival. Generation of new and removal of damaged or unwanted mitochondria are tightly controlled processes that need to be accurately coordinated for the maintenance of mitochondrial and cellular homeostasis. Mitophagy is a conserved, mitochondria-specific autophagic clearance process. An intricate regulatory network balances mitophagy with mitochondrial biogenesis. Proper coordination of these opposing processes is important for stress resistance and longevity. Age-dependent decline of mitophagy both inhibits removal of dysfunctional or superfluous mitochondria and impairs mitochondrial biogenesis resulting in progressive mitochondrial accretion and consequently, deterioration of cell function. Nodal regulatory factors that contribute to mitochondrial homeostasis have been implicated in the pathogenesis of several age-associated pathologies, such as neurodegenerative and cardiovascular disorders and cancer, among others. Thus, mitophagy is emerging as a potential target for therapeutic interventions against diseases associated with ageing. In this review, we survey the molecular mechanisms that govern and interface mitophagy with mitochondrial biogenesis, focusing on key elements that hold promise for the development of pharmacological approaches towards enhancing healthspan and quality of life in the elderly.

Introduction

Mitochondria are semi-autonomous organelles of prokaryotic origin. During evolution, mitochondria became integral part of the eukaryotic cell, procedure mediated by endosymbiosis billions of years ago. Their number varies in a cell type-specific manner and is spanning from a single up to several thousand mitochondria. Mitochondria contain their own genome composed of only 37 genes in humans, 13 of which encode mitochondrial proteins and the rest tRNAs and rRNAs important for the prokaryotic type of translation taking place inside the organelle matrix. Although mitochondria contain their own genome, their replication and proper function are tightly coupled to the import of nuclear encoded transcripts. Importantly, many of these molecules exhibit selective subcellular localization only in/on mitochondria.

The importance of mitochondria for the eukaryotic cell is highlighted not only by their involvement in vital functions that regulate cellular metabolism, but also by the consequences accompanying mitochondrial dysfunction or damage. More specifically, mitochondria play a key role in adenosine triphosphate (ATP) production, which is the main energy source of the cell. ATP production depends on aerobic respiration and oxidative phosphorylation that is mediated by the electron transport chain (ETC) components located in the inner mitochondrial membrane (IMM). In addition, mitochondria participate in several other functions contributing to calcium homeostasis, lipid metabolism and apoptotic cell death regulation as well as the control of the inflammation response (Kim et al., 2016a, Nicholls, 2005, Picard et al., 2015, Tait and Green, 2010, Zhang et al., 2010). Cell type-specific mitochondrial functions include thermogenesis regulation in brown adipose tissue, ammonia detoxification in liver cells and hormone biogenesis, among others (Lee et al., 2015, Soria et al., 2013, Velarde, 2014).

Mitochondrial malfunction is often multifactorial and is manifested by the production of aberrant amounts of ATP and reactive oxygen species (ROS). In most cases, ATP shortage and excessive ROS production due to ETC defects initiate a cascade of cellular events, leading to mitochondrial dysfunction and disruption of cellular homeostasis (Fig. 1A). Indeed, excessive generation of mitochondrial ROS (mtROS) such as superoxide causes mitochondrial DNA (mtDNA) mutations and damage on both mitochondrial and cytoplasmic proteins. Impaired mitochondrial homeostasis has been associated with several human syndromes and age-related diseases such as poor growth and developmental delays, liver and cardiac disease, seizures, infection susceptibility, cancer and various neurological and muscle disorders (Arnoult et al., 2009, Fillano et al., 2002, Oka et al., 2012, Vyas et al., 2016, Zsurka and Kunz, 2015). Mitochondrial-related disorders become more pronounced with advancing age followed by a proportional accumulation of mitochondria. The reason of mitochondrial accrual during ageing was identified as the decline in the efficiency of clearance mechanisms that selectively target mitochondria (Fig. 1A) (Palikaras et al., 2015b, Rubinsztein et al., 2011). Elucidation of the molecular mechanisms mediating the removal of dysfunctional organelles is the main goal of research in the field of autophagy.

Macroautophagy (hereafter, autophagy) is the most extensively studied type of autophagy (the other two are microautophagy and chaperone-mediated autophagy) and the process is highly conserved among eukaryotes (Glick, Barth, & Macleod, 2010). Such a self-consuming pathway has not been identified yet in prokaryotes but an upcoming evolutionary theory relative to the origin of autophagy, places it in the same conceptual framework with protophagy, a prokaryotic process sharing common features with autophagy (Starokadomskyy & Dmytruk, 2013). Autophagy's prerequisite and discriminative characteristic is the formation of a double-membrane vesicle, the autophagosome, which engulfs superfluous or deleterious cytoplasmic material such as proteins, whole organelles or inflammatory intruders. After its formation is completed, autophagosome fuses with the lysosome and the sequestered cargo is driven for hydrolytic degradation. The resulting degradation products are released back into the cytosol for re-use (Feng, He, Yao, & Klionsky, 2014). Autophagy is divided into two subclasses depending on its cargo: 1. Non-selective, that randomly degrades cytoplasmic material and 2. Selective, that recognizes and degrades specific organelles, including mitochondria (mitophagy), peroxisomes (pexophagy), the nucleus (nucleophagy), among others, or microbes (xenophagy) (Jin et al., 2013, Mochida et al., 2015). Selective autophagy requires specific cargo recognition, which is mediated either by specific receptors that recognize and bind to ubiquitin chains, connecting, in turn, ubiquitinated substrates to autophagosomal proteins LC3 (microtubule-associated protein 1A/1B-light chain 3) and GABARAP (GABA type A receptor-associated protein) or by organelle receptors that lie on the organelle membrane and directly bind to LC3.

In particular, mitophagy (mitochondria-specific autophagy) functions at basal levels under normal conditions to degrade superfluous organelles, thus regulating mitochondrial number depending on the metabolic needs of the cell. Under stress conditions, mitophagy is triggered to target malfunctioning organelles for degradation, promoting cell survival (Palikaras et al., 2015b). Although mitophagy is a very efficient process for mitochondrial damage control, it should be noted that elaborate mechanisms have evolved to repair mitochondria and sustain energy homeostasis (Fig. 1A). These mitochondrial quality control mechanisms are activated prior to mitophagy and include: 1. mitochondrial fusion mechanisms which “dilute” the damage among healthy mitochondria, so malfunction is finally undetectable, 2. activation of the mitochondrial unfolded protein response (mtUPR) system to restore perturbed proteostasis inside mitochondria and 3. formation of mitochondrial derived vesicles, which engulf and isolate specific mitochondrial substrates and translocate them from mitochondria to lysosomes for degradation (Lu, 2009, Pellegrino et al., 2013, Sugiura et al., 2014). Under conditions of extensive and irreversible damage though, these mechanisms are unable to restore homeostasis so mitophagy is induced to eliminate dysfunctional organelles (Tian et al., 2016, Twig and Shirihai, 2011).

On the other hand, excessive or persistent mitophagy events and subsequent mitochondria shortage would also lead to impairments in mitochondrial function, contributing to disturbed homeostasis at both the cellular and whole organism level. It is widely accepted that normal cell function requires the presence of a definite functional mitochondrial population. As a result, following mitophagy and as a response to it, a mitochondrial biogenesis program is stimulated not only to balance mitochondrial loss but also to replace the defective organelles by functional ones (Palikaras et al., 2015b). Mitochondrial biogenesis is a complex process that involves the activation of transcription programs in the nucleus and a variety of post-transcriptional events taking place both in the cytoplasm and inside mitochondria (Dominy and Puigserver, 2013, Fox, 2012).

The onset of severe age-related pathologies has been clearly linked with mitochondrial dysfunction. Better understanding of mitochondrial turnover mechanisms is a key requirement for the development of more efficient therapeutic strategies to battle numerous pathological conditions in humans. Here, we summarize important features of these mechanisms both under physiological and disease conditions as well as novel pharmacological agents that have been proposed for the treatment of such mitochondrial-related diseases. Finally, we discuss the future perspectives on the field.

Section snippets

Mechanisms of selective mitochondrial autophagy

Mitophagy was first reported in 2005 and since then it has largely attracted the interest of the scientific community (Lemasters, 2005). To date, several mitophagy mechanisms have been identified and additional novel regulators and mechanistic details on the field have started to emerge in several model organisms, highlighting mitophagy conservation (Table 1). In the following paragraphs, we describe the basic molecular mechanisms mediating mitophagy, with emphasis on latest research that shed

Mitophagy in pathological conditions

Several molecular pathways stimulate mitophagy to adjust mitochondrial population in response to physiological demands, intracellular and/or environmental signals. Deregulation of these molecular mechanisms alters the tight coordination between mitochondrial biogenesis and elimination leading to energy homeostasis collapse and eventually to cellular dysfunction (Fig. 1B). A variety of human pathological conditions, including tumorigenesis, hepatic and kidney failure, cardiovascular diseases,

Mitophagy modulators: new therapeutics of mitochondrial-related diseases

Impaired mitochondrial activity is a shared hallmark of diverse age-associated pathologies. Numerous quality control mechanisms are implicated in the maintenance of mitochondrial network integrity and function, including mitochondrial biogenesis and mitophagy, among others. General and selective mitochondrial autophagy could be a potential target for therapeutic interventions against age-associated disorders, which are characterized by impaired mitochondrial homeostasis. Several

Conclusions and future perspectives

Altered mitochondrial homeostasis characterized by low ATP levels, elevated cytoplasmic calcium and excessive ROS generation are the main key features of several pathological conditions and ageing. Additionally, accumulation of defective mitochondria is supposed to be the first-in class cause of the age-associated disorders, including neurodegenerative diseases, cardiomyopathies and cancer. Therefore, efficient mitochondrial quality control is pivotal for cellular and organismal homeostasis.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

We apologize to those colleagues whose work could not be referenced owing to space limitations. K.P. is supported by a Bodosaki Foundation long-term fellowship. Work in the authors' laboratory is also funded by grants from the European Commission Framework Programmes and the Greek Ministry of Education.

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