The Role of Mitochondrial Quality Control in Cognitive Dysfunction in Diabetes

Type 2 diabetes (T2DM) is a well known risk factor for Alzheimer’s disease. Mitochondria are the center of intracellular energy metabolism and the main source of reactive oxygen species. Mitochondrial dysfunction has been identified as a key factor in diabetes-associated brain alterations contributing to neurodegenerative events. Defective insulin signaling may act in concert with neurodegenerative mechanisms leading to abnormalities in mitochondrial structure and function. Mitochondrial dysfunction triggers neuronal energy exhaustion and oxidative stress, leading to brain neuronal damage and cognitive impairment. The normality of mitochondrial function is basically maintained by mitochondrial quality control mechanisms. In T2DM, defects in the mitochondrial quality control pathway in the brain have been found to lead to mitochondrial dysfunction and cognitive impairment. Here, we discuss the association of mitochondrial dysfunction with T2DM and cognitive impairment. We also review the molecular mechanisms of mitochondrial quality control and impacts of mitochondrial quality control on the progression of cognitive impairment in T2DM.

     

线粒体质量控制与米色脂肪之间的关系

近年来,肥胖患病率不断上升,肥胖已成为全球性公共卫生问题.肥胖能够增加高血压、冠心病等心血管疾病的发病风险,防治肥胖已经成为亟待解决的社会问题.米色脂肪是一种产热型脂肪细胞,可在受到寒冷、药物、运动等外界刺激下由白色脂肪细胞转化而来,但其形态和功能却与白色脂肪细胞不同,而与棕色脂肪细胞类似,即米色脂肪同样含有丰富的线粒...     

Alterations in mitochondrial morphology as a key driver of immunity and host defence

Mitochondria are dynamic organelles whose architecture changes depending on the cell’s energy requirements and other signalling events. These structural changes are collectively known as mitochondrial dynamics. Mitochondrial dynamics are crucial for cellular functions such as differentiation, energy production and cell death. Importantly, it has become clear in recent years that mitochondrial dynamics are a critical control point for immune cell function. Mitochondrial remodelling allows quiescent immune cells to rapidly change their metabolism and become activated, producing mediators, such as cytokines, chemokines and even metabolites to execute an effective immune response. The importance of mitochondrial dynamics in immunity is evident, as numerous pathogens have evolved mechanisms to manipulate host cell mitochondrial remodelling in order to promote their own survival. In this review, we comprehensively address the roles of mitochondrial dynamics in immune cell function, along with modulation of host cell mitochondrial morphology during viral and bacterial infections to facilitate either pathogen survival or host immunity. We also speculate on what the future may hold in terms of therapies targeting mitochondrial morphology for bacterial and viral control.     

Mieap与线粒体的质量控制

线粒体在细胞能量代谢和细胞凋亡中起着至关重要的作用.质量控制是线粒体在细胞中维持正常状态的关键机制.2011年Miyamoto等发现Mieap参与线粒体质量控制的两个新机制.Mieap诱导的溶酶体样细胞器,进入线粒体内,并在线粒体积累,能通过特异性的清除氧化的线粒体蛋白来修复异常线粒体,使得线粒体维持在正常状态.Mieap诱导的通过细胞膜内吞机制形成的囊泡,识别异常线粒体,并对其特异性的清除.Mieap诱导的这两个过程参与了线粒体质量控制,并决定线粒体的命运.     

Emerging roles of mitochondrial proteases in neurodegeneration

Fine tuning of integrated mitochondrial functions is essential in neurons and rationalizes why mitochondrial dysfunction plays an important pathogenic role in neurodegeneration. Mitochondria can contribute to neuronal cell death and axonal dysfunction through a plethora of mechanisms, including low ATP levels, increased reactive oxygen species, defective calcium regulation, and impairment of dynamics and transport. Recently, mitochondrial proteases in the inner mitochondrial membrane have emerged as culprits in several human neurodegenerative diseases. Mitochondrial proteases degrade misfolded and non-assembled polypeptides, thus performing quality control surveillance in the organelle. Moreover, they regulate the activity of specific substrates by mediating essential processing steps. Mitochondrial proteases may be directly involved in neurodegenerative diseases, as recently shown for the m-AAA protease, or may regulate crucial mitochondrial molecules, such as OPA1, which in turn is implicated in human disease. The mitochondrial proteases HTRA2 and PARL increase the susceptibility of neurons to apoptotic cell death. Here we review our current knowledge on how disturbances of the mitochondrial proteolytic system affect neuronal maintenance and axonal function.     

Implication of liver cardiolipins in mitochondrial energy metabolism disorder in cancer cachexia

Mitochondrial membranes are essential for the good functioning of the organelle. For instance, the inner mitochondrial membrane contains the oxidative phosphorylation system that permits ATP synthesis. Phospholipids environment and especially cardiolipin are crucial for the mitochondrial energy metabolism. Indeed, cardiolipin is known to provide essential structural and functional support to several proteins involved in oxidative phosphorylation. Alterations in cardiolipin structure, content and fatty acids composition have been associated with mitochondrial dysfunction in several physiopathological conditions and diseases. Cancer cachexia is a complex and dynamic process characterized by a negative energy balance induced by anorexia and hypermetabolism which leads to a drastic loss in body weight that aggravate prognosis of cancer patients. The underlying mechanisms of hypermetabolism are not fully understood. Whether the mitochondrial energy metabolism is altered during this disease and may participate to hypermetabolism is not clear. This mini-review focuses on cardiolipin especially its biosynthesis and remodeling pathways, its relation with mitochondrial energy metabolism and its possible implication in the cancer cachexia syndrome.     

Mitochondrial turnover in the heart

Mitochondrial quality control is increasingly recognized as an essential element in maintaining optimally functioning tissues. Mitochondrial quality control depends upon a balance between biogenesis and autophagic destruction. Mitochondrial dynamics (fusion and fission) allows for the redistribution of mitochondrial components. We speculate that this permits sorting of highly functional components into one end of a mitochondrion, while damaged components are segregated at the other end, to be jettisoned by asymmetric fission followed by selective mitophagy. Ischemic preconditioning requires autophagy/mitophagy, resulting in selective elimination of damaged mitochondria, leaving behind a population of robust mitochondria with a higher threshold for opening of the mitochondrial permeability transition pore. In this review we will consider the factors that regulate mitochondrial biogenesis and destruction, the machinery involved in both processes, and the biomedical consequences associated with altered mitochondrial turnover. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.

Research Highlights

?Mitochondrial quality control is accomplished by balanced destruction and production. ?Fission and fusion are essential for mitochondrial quality control. ?Mitophagy is mediated by Bnip3, Nix, Parkin, PINK1, and p62/SQSTM1. ?Impaired mitochondrial dynamics results in human disease. ?Mitophagy enables cardioprotection and metabolic reprogramming.     

Processing of mitochondrial presequences

Mitochondrial proteins are synthesized as precursor proteins on either cytosolic or mitochondrial ribosomes. The synthesized precursors from both translation origins possess targeting signals that guide the protein to its final destination in one of the four subcompartments of the organelle. The majority of nuclear-encoded mitochondrial precursors and also mitochondrial-encoded preproteins have an N-terminal presequence that serves as a targeting sequence. Specific presequence peptidases that are found in the matrix, inner membrane and intermembrane space of mitochondria proteolytically remove the signal sequence upon import or sorting. Besides the classical presequence peptidases MPP, IMP and Oct1, several novel proteases have recently been described to possess precursor processing activity, and analysis of their functional relevance revealed a tight connection between precursor processing, mitochondrial dynamics and protein quality control. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.     

Mitochondrial quality control pathways as determinants of metabolic health

Mitochondrial function is key for maintaining cellular health, while mitochondrial failure is associated with various pathologies, including inherited metabolic disorders and age‐related diseases. In order to maintain mitochondrial quality, several pathways of mitochondrial quality control have evolved. These systems monitor mitochondrial integrity through antioxidants, DNA repair systems, and chaperones and proteases involved in the mitochondrial unfolded protein response. Additional regulation of mitochondrial function involves dynamic exchange of components through mitochondrial fusion and fission. Sustained stress induces a selective autophagy – termed mitophagy – and ultimately leads to apoptosis. Together, these systems form a network that acts on the molecular, organellar, and cellular level. In this review, we highlight how these systems are regulated in an integrated context‐ and time‐dependent network of mitochondrial quality control that is implicated in healthy aging.     

Mitochondrial quality control in cardiac cells: Mechanisms and role in cardiac cell injury and disease

Mitochondria play an important role in maintaining cardiac homeostasis by supplying the major energy required for cardiac excitation–contraction coupling as well as controlling the key intracellular survival and death pathways. Healthy mitochondria generate ATP molecules through an aerobic process known as oxidative phosphorylation (OXPHOS). Mitochondrial injury during myocardial infarction (MI) impairs OXPHOS and results in the excessive production of reactive oxygen species (ROS), bioenergetic insufficiency, and contributes to the development of cardiovascular diseases. Therefore, mitochondrial biogenesis along with proper mitochondrial quality control machinery, which removes unhealthy mitochondria is pivotal for mitochondrial homeostasis and cardiac health. Upon damage to the mitochondrial network, mitochondrial quality control components are recruited to segregate the unhealthy mitochondria and target aberrant mitochondrial proteins for degradation and elimination. Impairment of mitochondrial quality control and accumulation of abnormal mitochondria have been reported in the pathogenesis of various cardiac disorders and heart failure. Here, we provide an overview of the recent studies describing various mechanistic pathways underlying mitochondrial homeostasis with the main focus on cardiac cells. In addition, this review demonstrates the potential effects of mitochondrial quality control dysregulation in the development of cardiovascular disease.     

Ubiquitin-dependent mitochondrial protein degradation

Progressive mitochondrial failure is tightly associated with the onset of many age-related human pathologies. This tight connection results from the double-edged sword of mitochondrial respiration, which is responsible for generating both ATP and ROS, as well as from risks that are inherent to mitochondrial biogenesis. To prevent and treat these diseases, a precise understanding of the mechanisms that maintain functional mitochondria is necessary. Mitochondrial protein quality control is one of the mechanisms that protect mitochondrial integrity, and increasing evidence implicates the cytosolic ubiquitin/proteasome system (UPS) as part of this surveillance network. In this review, we will discuss our current understanding of UPS-dependent mitochondrial protein degradation, its roles in diseases progression, and insights into future studies.     

线粒体融合/分裂对线粒体的质量控制作用

线粒体是一种结构和功能复杂而敏感的细胞器,拥有独立于细胞核的基因组,在细胞的不同时相,生理过程和环境条件下,线粒体的形态,数量和质量,具有高度的可塑性。线粒体是细胞和生物体内最主要的能量供应场所,几乎存在于所有种类的细胞中,是一种动态变化的细胞器。正常情况下,线粒体的数量、形态以及功能维持相对稳定的状态,称之为线粒体稳态。当上述状态发生紊乱时,细胞乃至生物体形态、功能也将受到影响甚至死亡。线粒体质量控制是在细胞中维持正常状态的关键机制,决定着线粒体的命运。近年,随着线粒体研究的深入和具体,逐渐发现融合/分裂在其形态、数量、遗传物质等质量控制相关的方面挥了重要作用。本文通过探讨融合/分裂对线粒体质量控制的作用机制,总结和讨论相关前沿研究,为后期研究提供一定的理论依据。     

Mitochondrial quality control: a matter of life and death for neurons

Neuronal survival critically depends on the integrity and functionality of mitochondria. A hierarchical system of cellular surveillance mechanisms protects mitochondria against stress, monitors mitochondrial damage and ensures the selective removal of dysfunctional mitochondrial proteins or organelles. Mitochondrial proteases emerge as central regulators that coordinate different quality control (QC) pathways within an interconnected network of mechanisms. A failure of this system causes neuronal loss in a steadily increasing number of neurodegenerative disorders, which include Parkinson's disease, spinocerebellar ataxia, spastic paraplegia and peripheral neuropathies. Here, we will discuss the role of the mitochondrial QC network for neuronal survival and neurodegeneration.     

Mfn2 is critical for brown adipose tissue thermogenic function

Mitochondrial fusion and fission events, collectively known as mitochondrial dynamics, act as quality control mechanisms to ensure mitochondrial function and fine‐tune cellular bioenergetics. Defective mitofusin 2 (Mfn2) expression and enhanced mitochondrial fission in skeletal muscle are hallmarks of insulin‐resistant states. Interestingly, Mfn2 is highly expressed in brown adipose tissue (BAT), yet its role remains unexplored. Using adipose‐specific Mfn2 knockout (Mfn2‐adKO) mice, we demonstrate that Mfn2, but not Mfn1, deficiency in BAT leads to a profound BAT dysfunction, associated with impaired respiratory capacity and a blunted response to adrenergic stimuli. Importantly, Mfn2 directly interacts with perilipin 1, facilitating the interaction between the mitochondria and the lipid droplet in response to adrenergic stimulation. Surprisingly, Mfn2‐adKO mice were protected from high‐fat diet‐induced insulin resistance and hepatic steatosis. Altogether, these results demonstrate that Mfn2 is a mediator of mitochondria to lipid droplet interactions, influencing lipolytic processes and whole‐body energy homeostasis.