Mitochondrial ROS Produced by Skeletal Muscle Mitochondria Promote the Decisive Signal for UPRmt Activation

Abstract

The mitochondrial unfolded protein response (UPRmt) can repair and remove misfolded or unfolded proteins in mitochondria and enhance mitochondrial protein homeostasis. Reactive oxygen species (ROS) produced by regular exercise is a crucial signal for promoting health, and skeletal muscle mitochondria are the primary source of ROS during exercise. To verify whether UPRmt is related to ROS produced by mitochondria in skeletal muscle during regular exercise, we adapted MitoTEMPO, mitochondrially targeted antioxidants, and ROS production by mitochondria. Our results showed that mitochondrial ROS is the key factor for activating UPRmt in different pathways.

Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle

“…Additionally, studies have found that ATF5 plays a critical role in exercise-induced UPRmt and mitochondrial homeostasis because ATF5-knockout muscle displays an enhanced exercise-induced stress kinase signaling response but a blunted UPRmt and mitophagic gene expression response [112]. More recently, our group found that just 12 days of exercise is sufficient for increasing the expression of c-Jun, HSP60, and CLpP in mouse skeletal muscle, which strongly suggests the activation of the classical UPRmt pathway [113]. These results collectively highlight the effectiveness of exercise in promoting the activation of the UPRmt pathway in skeletal muscle.…”

“…This finding contrasts with antioxidant intervention, which inhibits oxidative stress and induces a low-level redox balance, reducing or abolishing exercise-associated stress and preventing the health-promoting effects of exercise. Our group recently demonstrated that inhibiting mitochondrial ROS generation in mice during exercise using MitoTEMPO, a novel cell-penetrating antioxidant targeting mitochondria, reduces the increases in the c-Jun, HSP60, and CLpP levels in the classical pathway of the UPRmt in skeletal muscle, indicating that exercise-derived ROS stimulate the UPRmt [113]. Additionally, an acute burst of ROS from mitochondria induced by the mitochondrial-targeted photosensitizer KillerRed results in the activation of Parkin-dependent mitophagy [129].…”

Activation of the mitochondrial unfolded protein response regulates the formation of stress granules

“…The disruption of mitochondrial homeostasis is associated with several pathologies, such as neurodegeneration, cancer, aging, and cardiovascular diseases (Chen et al, 2023; Norat et al, 2020; Quirós et al, 2016; Suomalainen and Battersby, 2018). The UPRmt is an evolutionarily conserved homeostatic pathway engaged upon a wide range of mitochondrial insults, including mitochondrial protein misfolding (Zhao et al, 2002), reduced mitochondrial protein import efficiency (Nargund et al, 2012), dissipation of mitochondrial membrane potential (Donehower et al, 2019), and dysregulated levels of reactive oxygen species (ROS) (Wang et al, 2022b). UPRmt activation triggers a broad and protective transcriptional cascade, through enhancing mitochondrial folding capacity and triggering a mitochondrial recovery program, alleviating neurodegenerative and cardiovascular diseases symptomatology (Smyrnias et al, 2019; Sorrentino et al, 2017), promoting resistance to pathogen infection (Mahmud et al, 2020; Pellegrino et al, 2014), and prolonging lifespan (Munkácsy and Rea, 2014).…”

“…Key to maintaining or adapting mitochondrial functions, the mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved mitochondria-to-nucleus signalling cascade, initially described as a transcriptional response to the accumulation of misfolded mitochondrial proteins (Martinus et al, 1996; Zhao et al, 2002). Studies have shown that activation of the UPRmt is primarily regulated by the Activating Transcription Factor 5 (ATF5) (Fiorese et al, 2016; Smyrnias et al, 2019; Wang et al, 2019), and engaged upon a wide range of mitochondrial insults, including abnormal level of mitochondrial reactive oxygen species (ROS) (Wang et al, 2022b), dissipation of mitochondrial membrane potential (Rolland et al, 2019), and reduced mitochondrial protein import efficiency (Nargund et al, 2012). Activated UPRmt serves to restore mitochondrial protein homeostasis and promote cell survival in various biological processes, such as innate immune signalling (Pellegrino et al, 2014) and ageing (Houtkooper et al, 2013), as well as adaptation to pathophysiological conditions, such as neurodegenerative disorders (Sorrentino et al, 2017) and cardiovascular diseases (Smyrnias et al, 2019; Wang et al, 2019).…”

Impact of Exercise and Aging on Mitochondrial Homeostasis in Skeletal Muscle: Roles of ROS and Epigenetics

“…Daily intake of vitamins C and E almost completely eliminated the changes in the expression of these genes and the increase in insulin sensitivity after exercise [129]. Recently, Wang et al [130] demonstrated that regular exercise could activate UPRmt and increase the content of SOD2. However, the expression of c-JUN, the C/EBP homologous protein, HSP60, CLpP, SIRT3, hightemperature-regulated A2 (also known as OMI), and SOD2 decreased after intervention with mitochondrial-derived ROS (mtROS) with the mitochondria-targeted antioxidant MitoTEMPO.…”