Mitochondrial dysfunction and quality control lie at the heart of subarachnoid hemorrhage

The dramatic increase in intracranial pressure after subarachnoid hemorrhage leads to a decrease in cerebral perfusion pressure and a reduction in cerebral blood flow.Mitochondria are directly affected by direct factors such as ischemia,hypoxia,excitotoxicity,and toxicity of free hemoglobin and its degradation products,which trigger mitochondrial dysfunction.Dysfunctional mitochondria release large amounts of reactive oxygen species,inflammatory mediators,and apoptotic proteins that activate apoptotic pathways,further damaging cells.In response to this array of damage,cells have adopted multiple mitochondrial quality control mechanisms through evolution,including mitochondrial protein quality control,mitochondrial dynamics,mitophagy,mitochondrial biogenesis,and intercellular mitochondrial transfer,to maintain mitochondrial homeostasis under pathological conditions.Specific interventions targeting mitochondrial quality control mechanisms have emerged as promising therapeutic strategies for subarachnoid hemorrhage.This review provides an overview of recent research advances in mitochondrial pathophysiological processes after subarachnoid hemorrhage,particularly mitochondrial quality control mechanisms.It also presents potential therapeutic strategies to target mitochondrial quality control in subarachnoid hemorrhage.

Mitochondrial quality control mechanisms as molecular targets in cardiac ischemia-reperfusion injury

Mitochondrial damage is a critical contributor to cardiac ischemia/reperfusion(I/R)injury.Mitochondrial quality control(MQC)mechanisms,a series of adaptive responses that preserve mitochondrial structure and function,ensure cardiomyocyte survival and cardiac function after I/R injury.MQC includes mitochondrial fission,mitochondrial fusion,mitophagy and mitochondria-dependent cell death.The interplay among these responses is linked to pathological changes such as redox imbalance,calcium overload,energy metabolism disorder,signal transduction arrest,the mitochondrial unfolded protein response and endoplasmic reticulum stress.Excessive mitochondrial fission is an early marker of mitochondrial damage and cardiomyocyte death.Reduced mitochondrial fusion has been observed in stressed cardiomyocytes and correlates with mitochondrial dysfunction and cardiac depression.Mitophagy allows autophagosomes to selectively degrade poorly structured mitochondria,thus maintaining mitochondrial network fitness.Nevertheless,abnormal mitophagy is maladaptive and has been linked to cell death.Although mitochondria serve as the fuel source of the heart by continuously producing adenosine triphosphate,they also stimulate cardiomyocyte death by inducing apoptosis or necroptosis in the reperfused myocardium.Therefore,defects in MQC may determine the fate of cardiomyocytes.In this review,we summarize the regulatory mechanisms and pathological effects of MQC in myocardial I/R injury,highlighting potential targets for the clinical management of reperfusion.

Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer’s disease

Aging is by far the most prominent risk factor for Alzheimer’s disease(AD),and both aging and AD are associated with apparent metabolic alterations.As developing effective therapeutic interventions to treat AD is clearly in urgent need,the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients,on disease pathogenesis,have been explored.There is also an increasing awareness of differential risk and potential targeting strategies related to biological sex,microbiome,and circadian regulation.As a major part of intracellular metabolism,mitochondrial bioenergetics,mitochondrial quality-control mechanisms,and mitochondria-linked inflammatory responses have been considered for AD therapeutic interventions.This review summarizes and highlights these efforts.

Ubiquitin phosphorylation in Parkinson’s disease:Implications for pathogenesis and treatment

Parkinson’s disease(PD)is the most common neurodegenerative movement disorder,characterized primarily by the loss of dopaminergic neurons in substantia nigra.The pathogenic mechanisms of PD remain unclear,and no effective therapy currently exists to stop neurodegeneration in this debilitating disease.The identification of mutations in mitochondrial serine/threonine kinase PINK1 or E3 ubiquitin-protein ligase parkin as the cause of autosomal recessive PD opens up new avenues for uncovering neuroprotective pathways and PD pathogenic mechanisms.Recent studies reveal that PINK1 translocates to the outer mitochondrial membrane in response to mitochondrial depolarization and phosphorylates ubiquitin at the residue Ser65.The phosphorylated ubiquitin serves as a signal for activating parkin and recruiting autophagy receptors to promote clearance of damaged mitochondria via mitophagy.Emerging evidence has begun to indicate a link between impaired ubiquitin phosphorylation-dependent mitophagy and PD pathogenesis and supports the potential of Ser65-phosphorylated ubiquitin as a biomarker for PD.The new mechanistic insights and phenotypic screens have identified multiple potential therapeutic targets for PD drug discovery.This review highlights recent advances in understanding ubiquitin phosphorylation in mitochondrial quality control and PD pathogenesis and discusses how these findings can be translated into novel approaches for PD diagnostic and therapeutic development.