Mitochondrial proteostasis stress in muscle drives a long-range protective response to alleviate dietary obesity independently of ATF4

Abstract

Mitochondrial quality in skeletal muscle is crucial for maintaining energy homeostasis during metabolic stresses. However, how muscle mitochondrial quality is controlled and its physiological impacts remain unclear. Here, we demonstrate that mitoprotease LONP1 is essential for preserving muscle mitochondrial proteostasis and systemic metabolic homeostasis. Skeletal muscle–specific deletion of Lon protease homolog, mitochondrial (LONP1) impaired mitochondrial protein turnover, leading to muscle mitochondrial proteostasis stress. A benefit of this adaptive response was the complete resistance to diet-induced obesity. These favorable metabolic phenotypes were recapitulated in mice overexpressing LONP1 substrate ΔOTC in muscle mitochondria. Mechanistically, mitochondrial proteostasis imbalance elicits an unfolded protein response (UPR mt ) in muscle that acts distally to modulate adipose tissue and liver metabolism. Unexpectedly, contrary to its previously proposed role, ATF4 is dispensable for the long-range protective response of skeletal muscle. Thus, these findings reveal a pivotal role of LONP1-dependent mitochondrial proteostasis in directing muscle UPR mt to regulate systemic metabolism.

Increased mitochondrial surface area and cristae density in the skeletal muscle of strength athletes

“…We selected ‘resistance exercise studies’ and restricted the analyses to 0 to 6 hours post-exercise, without any other participant criteria, to obtain a high statistical power and a large sample size (n = 148). Genes from each of the pathways of interest (Figure 6.A) were manually curated based on previous literature (Pakos-Zebrucka et al ., 2016; Trewin et al ., 2018; Bishop et al ., 2019; Huertas et al ., 2019; Guo et al ., 2022).…”

“…Gene-set enrichment analyses (GSEA) was performed using the R package fast geneset enrichment analysis ( FGSEA ) (Korotkevich et al ., 2021). Mitochondrial-specific genesets were utilised (obtained from the MitoCarta 3.0 (Rath et al ., 2021)) and the mitochondrial unfolded protein response (UPR mt ) geneset was obtained from a mouse study (Guo et al ., 2022). An adjusted p-value lower than 0.05 was deemed significant and enrichment values are reported as normalised enrichment scores (NES).…”

The Role of Lonp1 on Mitochondrial Functions during Cardiovascular and Muscular Diseases

“…Several studies reported that Lonp1 ablation in mouse muscle induces UPRmt activation, leading to adipose tissue and liver metabolism modulation. Functionally, in this model not only the well-known mitochondrial protein turnover alterations can be observed, but also improved insulin resistance, reduced liver steatosis and prevention of high-fat diet (HFD)-induced obesity [ 135 ]. Furthermore, following Lonp1 ablation, muscles are forced to secrete myokines, especially FGF21 and GDF15, to exert endocrine effects, which can contrast diet-induced obesity and generates a positive effect on metabolism [ 136 , 137 , 138 , 139 , 140 ].…”

“…Guo and colleagues showed that, upon HFD feeding, Lonp1 knockout mice are characterized by reduced lean and fat mass, leading to lower body weight [ 101 , 135 ], smaller adipocytes in adipose tissue, higher mitochondrial respiration and oxidation, increased expressions of genes related to thermogenesis, and lipolysis. Conversely, there is a decrease in fatty acid synthase (FASN) protein levels and de novo lipogenesis, leading to protection from diet-induced hepatic steatosis.…”

“…Moreover, food intake is increased indicating a deficit in conversion of food into body mass when Lonp1 is downregulated. Therefore, Guo and colleagues proposed an important role of Lonp1 in modulating muscle adaptation under excess nutrient stress [ 135 ]. In addition, Lonp1 skeletal muscle-specific ablation upon HFD feeding triggers the induction of several UPRmt markers, suggesting that muscle UPRmt signals may have a protective effect, as they can regulate the communication between adipose tissue and the liver and alleviate dietary obesity.…”