RESUMO
Mitophagy is a process that selectively removes excess or damaged mitochondria and plays an important role in regulating intracellular mitochondrial mass and maintaining mitochondrial energy metabolism. TANK-binding kinase 1 (TBK1) is a multifunctional serine/threonine protein kinase, which is involved in the regulation of PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent and -independent mitophagy. Recent studies have shown that TBK1 phosphorylates the autophagy related proteins, such as optineurin (OPTN), p62/sequestosome-1, Ras-related GTP binding protein 7 (Rab7), and mediates the binding of nuclear dot protein 52 (NDP52) to UNC-51 like autophagy activating kinase 1 (ULK1) complex, as well as the binding of TAX1-binding protein 1 (TAX1BP1) to microtubule-associated protein 1 light chain 3 (LC3), thereby enhancing PINK1/Parkin-dependent mitophagy. In addition, TBK1 is a direct substrate of AMP-activated protein kinase (AMPK)/ULK1 pathway, and its activation phosphorylates dynamin-related protein 1 (Drp1) and Rab7 to promote PINK1/Parkin-independent mitophagy. This article reviews the role and mechanism of TBK1 in regulating PINK1/Parkin-dependent and -independent mitophagy.
Assuntos
Mitofagia , Ubiquitina-Proteína Ligases , Proteínas Quinases Ativadas por AMP , Autofagia , Metabolismo EnergéticoRESUMO
Cells selectively scavenge redundant or damaged mitochondria by mitophagy, which is an important mechanism of mitochondrial quality control. Recent studies have shown that mitophagy is mainly regulated by autophagy-related genes (Atgs) in yeast cells, while mitochondrial membrane associated proteins such as PTEN-induced putative kinase 1 (PINK1), NIX/BNIP3L, BNIP3, FUN14 domain containing 1 (FUNDC1), FKBP8/FKBP38, Bcl-2-like protein 13 (Bcl2L13), nucleotide binding domain and leucine-rich-repeat-containing proteins X1 (NLRX1), prohibitin 2 (PHB2) and lipids such as cardiolipin (CL) are the key mitophagic receptors in mammalian cells, which can selectively recognize damaged mitochondria, recruit them into isolation membranes by binding to microtubule-associated protein 1 light chain 3 (LC3) or γ-aminobutyric acid receptor-associated protein (GABARAP), and then fuse with lysosomes to eliminate the trapped mitochondria. This article reviews recent research progress of mitophagy-related receptor proteins.
Assuntos
Mitofagia , Proibitinas , Animais , Proteínas Reguladoras de Apoptose , Autofagia , Proteínas Associadas aos Microtúbulos , Mitocôndrias , Proteínas Mitocondriais/genéticaRESUMO
The imbalance of protein metabolism is the major cause of skeletal muscle atrophy, and the decrease of protein synthesis directly leads to the occurrence and development of age-related sarcopenia. The canonical role of leucyl-tRNA synthetase (LeuRS) is ligating leucine to the cognate tRNA, and thus it plays a central role in genetic coding. With the further studies of LeuRS in recent years, LeuRS has been found to control protein homeostasis in aging skeletal muscle via its non-canonical role. In this paper, we reviewed the structure and biological features of aminoacyl-tRNA synthetase and LeuRS, and summarized the recent advances in studies on the effects of LeuRS in regulating aging skeletal muscle protein synthesis as an intracellular leucine sensor. Moreover, we also analyzed the potential role of LeuRS in activation of mammalian target of rapamycin complex 1 (mTORC1) signaling transduction pathway in response to anabolic stimuli such as exercise and amino acids ingestion. This paper may provide some new ideas for the prevention, diagnosis and treatment of age-related sarcopenia.
Assuntos
Aminoacil-tRNA Sintetases/genética , Leucina-tRNA Ligase/genética , Músculo Esquelético , Biossíntese de ProteínasRESUMO
Sarcopenia is defined as the progressive loss of muscle mass with age, and poses a serious threat to the physiological and psychological health of the elderly population with consequential economic and social burdens. Chronic low-grade inflammation plays a central role in the development of sarcopenia such that it alters cellular protein metabolism to favor proteolysis over synthesis, and thereby accelerates muscular atrophy. The purpose of this review is to highlight how exercise and nutrition intervention strategies can attenuate or treat sarcopenia. Resistance exercise increases not only muscle mass but also muscle strength, while aerobic exercise is able to ameliorate the age-related metabolic disorders. Concurrent exercise training integrates the advantages of both aerobic and resistance exercise, and may exert a significant synergistic effect in the aging organism. Higher protein intakes rich in the amino acid leucine appear to restore skeletal muscle protein metabolism balance by rescuing protein synthesis in older adults. There is good reason to believe that a multimodal treatment, a combination of exercise and increased leucine consumption in the diet, can combat some of the muscle loss associated with aging. Future research is needed to consolidate these findings to humans, and to further clarify to what extent and by which mechanisms protein metabolism might be directly involved in sarcopenia pathogenesis and the multimodal treatment responses.
RESUMO
Several studies have indicated a positive influence of leucine supplementation and aerobic training on the aging skeletal muscle signaling pathways that control muscle protein balance and muscle remodeling. However, the effect of a combined intervention requires further clarification. Thirteen month old CD-1(®) mice were subjected to moderate aerobic exercise (45 min swimming per day with 3% body weight workload) and fed a chow diet with 5% leucine or 3.4% alanine for 8 weeks. Serum and plasma were prepared for glucose, urea nitrogen, insulin and amino acid profile analysis. The white gastrocnemius muscles were used for determination of muscle size and signaling proteins involved in protein synthesis and degradation. The results show that both 8 weeks of leucine supplementation and aerobic training elevated the activity of mTOR (mammalian target of rapamycin) and its downstream target p70S6K and 4E-BP1, inhibited the ubiquitin-proteasome system, and increased fiber cross-sectional area (CSA) in white gastrocnemius muscle. Moreover, leucine supplementation in combination with exercise demonstrated more significant effects, such as greater CSA, protein content and altered phosphorylation (suggestive of increased activity) of protein synthesis signaling proteins, in addition to lower expression of proteins involved in protein degradation compared to leucine or exercise alone. The current study shows moderate aerobic training combined with 5% leucine supplementation has the potential to increase muscle size in fast-twitch skeletal muscle during aging, potentially through increased protein synthesis and decreased protein breakdown.