Impact of mitophagy and mitochondrial unfolded protein response as new adaptive mechanisms underlying old pathologies: sarcopenia and non-alcoholic fatty liver disease

Abstract

Mitochondria are the first-line defense of the cell in the presence of stressing processes that can induce mitochondrial dysfunction. Under these conditions, the activation of two axes is accomplished, namely, (i) the mitochondrial unfolded protein response (UPRmt) to promote cell recovery and survival of the mitochondrial network; (ii) the mitophagy process to eliminate altered or dysfunctional mitochondria. For these purposes, the former response induces the expression of chaperones, proteases, antioxidant components and protein import and assembly factors, whereas the latter is signaled through the activation of the PINK1/Parkin and BNIP3/NIX pathways. These adaptive mechanisms may be compromised during aging, leading to the development of several pathologies including sarcopenia, defined as the loss of skeletal muscle mass and performance; and non-alcoholic fatty liver disease (NAFLD). These age-associated diseases are characterized by the progressive loss of organ function due to the accumulation of reactive oxygen species (ROS)-induced damage to biomolecules, since the ability to counteract the continuous and large generation of ROS becomes increasingly inefficient with aging, resulting in mitochondrial dysfunction as a central pathogenic mechanism. Nevertheless, the role of the integrated stress response (ISR) involving UPRmt and mitophagy in the development and progression of these illnesses is still a matter of debate, considering that some studies indicate that the prolonged exposure to low levels of stress may trigger these mechanisms to maintain mitohormesis, whereas others sustain that chronic activation of them could lead to cell death. In this review, we discuss the available research that contributes to unveil the role of the mitochondrial UPR in the development of sarcopenia, in an attempt to describe changes prior to the manifestation of severe symptoms; and in NAFLD, in order to prevent or reverse fat accumulation and its progression by means of suitable protocols to be addressed in future studies.