线粒体自噬影响胰岛素抵抗的作用及机制

The Effect and Mechanism of Mitophagy on Insulin Resistance

胰岛素抵抗(IR)是诱发许多代谢疾病的关键因素,包括代谢综合征、非酒精性脂肪性肝病、动脉粥样硬化和2型糖尿病(T2DM)。随着相关代谢疾病日益增多,寻找新的治疗靶点迫在眉睫。线粒体自噬是一种选择性自噬,其通过清除受损和功能失调的线粒体以维持正常线粒体功能和能量代谢。研究发现,线粒体自噬在代谢疾病中有积极作用,线粒体自噬受到各种信号通路与信号分子调控而改善代谢疾病,如AMPK/ULK1、PINK1/Parkin信号通路以及BNIP3/Nix和FUNDC1等信号分子。本文阐述了线粒体自噬在胰岛素抵抗中的作用及调控机制,综述了近年的相关研究进展。

Mitophagy,a highly precise form of autophagy,plays a pivotal role in maintaining cellular homeostasis by selectively targeting and eliminating damaged mitochondria through a process known as mitophagy.Within this tightly regulated mechanism,dysfunctional mitochondria are specifically delivered to lysosomes for degradation.Disruptions in mitophagy have been implicated in a diverse range of pathological conditions,spanning diseases of the nervous system,cardiovascular system,cancer,aging,and metabolic syndrome.The elucidation of mitophagy’s impact on cardiovascular disorders,liver diseases,metabolic syndromes,immune dysfunctions,inflammatory conditions,and cancer has significantly advanced our understanding of the complex pathogenesis underlying these conditions.These studies have shed light on the intricate connections between dysfunctional mitophagy and disease progression.Among the disorders associated with mitochondrial dysfunction,insulin resistance(IR)stands out as a prominent condition linked to metabolic disorders.IR is characterized by a diminished response to normal levels of insulin,necessitating higher insulin levels to trigger a typical physiological reaction.Hyperinsulinemia and metabolic disturbances often coexist with IR,primarily due to defects in insulin signal transduction.Oxidative stress,stemming from mitochondrial dysfunction,exerts dual effects in the context of IR.Initially,it disrupts insulin signaling pathways and subtly contributes to the development of IR.Additionally,by inducing mitochondrial damage and autophagy,oxidative stress indirectly impedes insulin signaling pathways.Consequently,mitophagy acts as a protective mechanism,encapsulating damaged or dysfunctional mitochondria through the autophagy-lysosome pathway.This efficient process eliminates excessive oxidative stress reactive.The intricate interplay between mitochondrial function,oxidative stress,mitophagy,and IR represents a captivating field of investigation in the realm of metabolic disorders.By unraveling the underlying complexities and comprehending the intricate relationships between these intertwined processes,researchers strive toward uncovering novel therapeutic strategies.With a particular focus on mitochondrial quality control and the maintenance of redox homeostasis,these interventions hold tremendous potential in mitigating IR and enhancing overall metabolic health.Emerging evidence from a myriad of studies has shed light on the active involvement of mitophagy in the pathogenesis of metabolic disorders.Notably,interventions such as exercise,drug therapies,and natural products have been documented to induce mitophagy,thereby exerting beneficial effects on metabolic health through the activation of diverse signaling pathways.Several pivotal signaling molecules,including AMPK,PINK1/Parkin,BNIP3/Nix,and FUNDC1,have been identified as key regulators of mitophagy and have been implicated in the favorable outcomes observed in metabolic disorders.Of particular interest is the unique role of PINK1/Parkin in mitophagy compared to other proteins involved in this process.PINK1/Parkin exerts influence on mitophagy through the ubiquitination of outer mitochondrial membrane proteins.Conversely,BNIP3/Nix and FUNDC1 modulate mitophagy through their interaction with LC3,while also displaying certain interrelationships with each other.In this comprehensive review,our objective is to investigate the intricate interplay between mitophagy and IR,elucidating the relevant signaling pathways and exploring the treatment strategies that have garnered attention in recent years.By assimilating and integrating these findings,we aim to establish a comprehensive understanding of the multifaceted roles and intricate mechanisms by which mitophagy influences IR.This endeavor,in turn,seeks to provide novel insights and serve as a catalyst for further research in the pursuit of innovative treatments targeting IR.