Mitochondrial Proteostatic Collapse Leads to Hypoxic Injury

Abstract

Summary Hypoxic injury is a key pathological event in a variety of diseases. Despite the clinical importance of hypoxia, modulation of hypoxic injury mechanisms for therapeutic benefit has not been achieved suggesting that critical features of hypoxic injury have not been identified or fully understood. As mitochondria are the main respiratory organelles of the cell they have been the focus of much research into hypoxic injury. Previous research has focused on mitochondria as effectors of hypoxic injury, primarily in the context of apoptosis activation [1] and calcium regulation [2]; however, little is known about how mitochondria themselves are injured by hypoxia. Maintenance of protein folding is essential for normal mitochondrial function [3], while failure to maintain protein homeostasis (proteostasis) appears to be a component of ageing [4, 5] and a variety of diseases [6, 7]. Previously it has been demonstrated that mitochondria possess their own unfolded protein response [8–10] that is activated in response to mitochondrial protein folding stress, a response that is best understood in C. elegans. As hypoxia has been shown to disrupt ATP production and translation of nuclear encoded proteins [11], both shown to disrupt mitochondrial proteostasis in other contexts [3, 12], we hypothesized that failure to maintain mitochondrial proteostasis may play a role in hypoxic injury. Utilizing C. elegans models of global [13, 14], focal [15], and cell non-autonomous hypoxic injury we have found evidence of mitochondrial protein misfolding post-hypoxia, and that manipulation of the mitochondrial protein folding environment is an effective hypoxia protective strategy.

Cell Biology of the Mitochondrion

“…The recovery was regulated by EGL-9 and HIF-1, and suggested that a conserved response to anoxic stress was in play. Kaufman and Crowder (2015) showed that resistance to anoxia involves mitochondrial proteostasis, and that manipulation of the mitochondrial unfolded protein response could be used to protect the nematode from anoxic lethality. Pena et al (2016) confirmed and extended this finding, showing that activation of the UPR mt either by drugs (ethidium bromide) or genetically [spg-7 and atfs-1(gf)] was sufficient to reduce lethality in response to anoxia in a reperfusion protocol.…”

“…T HERE has been a resurgence in interest in mitochondrial structure and function in recent years (Dancy et al 2015;Maglioni and Ventura 2016). This change is in part due to a growing appreciation of the role of mitochondria in multiple functions other than energy production (e.g., Ca ++ homeostasis (Sarasija and Norman 2015;Oxenoid et al 2016), generation of reactive oxidation species (ROS) (Hekimi et al 2016), regulation of apoptosis (Yee et al 2014), activation of endoplasmic reticulum (ER)-stress response (Kim et al 2016)), as well as other far-ranging sequelae of mitochondrial dysfunction (Kaufman and Crowder 2015;Fong et al 2016;Melentijevic et al 2017). Mitochondria are also implicated in many common diseases, like Alzheimer and Parkinson's disease (Ray et al 2014;Fong et al 2016), and in the process of normal aging (Wang and Hekimi 2015).…”

Alcohol induces mitochondrial fragmentation and stress responses to maintain normal muscle function in Caenorhabditis elegans

“…In addition to this metabolic adaption, ATFS-1 promotes oxidative phosphorylation complex assembly and an increase of protective mitochondrial chaperones and proteases designed to improve the health of mitochondrial proteome (9,34). Importantly, this global change is beneficial to certain types of stresses or infection (32,33,(35)(36)(37), but is potentially harmful to others (38,39). Intriguingly, skeletal muscles of chronic alcohol users were reported to exhibit a reduction of aerobic metabolism and an increase of anaerobic metabolism (40).…”

Hypoxia-Induced Degenerative Protein Modifications Associated with Aging and Age-Associated Disorders

“…These authors found destabilization of the junction between the membrane and matrix arm of mitochondria in AD. As evaluated by Kaufman and Crowder, [89] an increase in the detergent-soluble proteins, which are believed to be misfolded and aggregated, were the consequences of the hypoxic conditions. Thus, protein aggregation is common feature of aging and hypoxia and neurodegenerative diseases.…”