Targeting mitochondria for the treatment of neurodegenerative diseases

Mitochondrial Crossroads in Neurobiology: From Cellular Vulnerability to Therapeutic Opportunity

Mitochondria in health and disease: cellular powerhouses, signaling centers, and drivers of dysfunction

Recent studies demonstrate promising therapeutic targets for mitochondrial dysfunction and highlight the need for research in mitochondrial function to change the therapeutic landscape in the management of mitochondrial dysfunction-associated diseases.

Mitochondria-targeted natural products with potential for the treatment of mitochondria-related diseases.

This review systematically summarize the specific mitochondrial pathological phenotypes in various diseases and provides a comprehensive overview of natural products that correspond to these phenotypes, along with their mechanisms of action.

Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration

Regulation of mitochondrial health is critical for maintaining cellular homeostasis in the nervous system. Damaged mitochondria can have detrimental effects on neuronal health and are thought to be key contributors to the progression of neurodegenerative disorders including Parkinson’s disease and amyotrophic lateral sclerosis. To mitigate this damage, multiple quality control mechanisms have evolved to eliminate aged or damaged mitochondria. One such quality control process is autophagy, a process that involves turnover of mitochondria at presynaptic sites and the axon terminal under basal conditions. This highly conserved mechanism sequesters mitochondria from the cytosol within autophagosomes followed by degradation upon fusion with a lysosome. Acute mitochondrial damage activates a selective form of autophagy called mitophagy that involves receptor-mediated engulfment and degradation of the damaged organelle. Multiple mechanisms have been shown to drive efficient mitophagy in neurons and glia, including PTEN induced kinase 1 (PINK1)/Parkin–dependent mitophagy and receptor-mediated mitophagy. Genetic, pathological, and experimental evidence all implicate defects in the removal of damaged mitochondria in the onset or progression of neurodegenerative disease. Both the initiation of PINK1/Parkin–dependent mitophagy and deficits in the removal of damaged mitochondria are linked to activation of neuroinflammatory pathways, including NF-κB and cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) signaling. In this Review, we discuss the molecular pathways governing mitophagy in neurons and glial cells and how deficits in these pathways may lead to neurodegeneration. We also highlight emerging therapeutic strategies aimed at restoring mitophagy to preserve neuronal homeostasis and function.

Mitochondria as a therapeutic platform in inflammatory and degenerative disorders: mechanisms, biomarkers, and translational challenges.

This review focuses on the core mechanisms that link mitochondrial dysfunction to disease progression and the major barriers to translation, and examines biomarker development and the major barriers to translation.

Restoring mitochondria and associated chaperone function: New therapeutic strategies for neurodegenerative diseases.

Neurodegenerative diseases have emerged as a significant global health challenge, with existing treatments merely providing symptomatic relief and failing to halt disease progression. Mitochondrial dysfunction and an imbalance in the molecular chaperone network constitute the core common pathological mechanisms underlying various neurodegenerative diseases (NDDs). These two factors collaboratively induce energy metabolism disorders, oxidative stress, calcium homeostasis imbalance, and protein homeostasis collapse, collectively driving neuronal degeneration. This article systematically elucidates the core characteristics of mitochondrial dysfunction in NDDs, dissects the molecular mechanisms by which the mitochondrial molecular chaperone network maintains mitochondrial homeostasis, summarizes therapeutic strategies for NDDs aimed at restoring mitochondrial and related molecular chaperone functions, discusses the current challenges faced in research, such as targeted delivery and clinical translation, and also proposes potential development directions for future.