TL;DR
The latest research delineating the landscape and network of autophagy in developing and mature neurons is reviewed, elucidating how conserved autophagy pathways regulate neuronal homeostasis and functions at different ages.
This review synthesizes evidence from genetic, biochemical, and neuropathological studies to highlight shared molecular nodes, such as ESCRT-III components, the VPS4 ATPase, the adaptor protein ALIX, and late endosomal regulators, including Rab7 that couple membrane remodeling to autophagic flux.
The autophagy–lysosomal pathway is key for the removal of harmful substances in cells. This article integrates evidence that highlights the role of lysosomal function and the autophagy–lysosomal pathway in maintaining intracellular homeostasis and the effects of their dysfunction on protein secretion and metabolic disorders, leading to the pathogenesis of Alzheimer's disease (AD) and other tau diseases. Dysfunction of the autophagy-lysosomal pathway is believed to be the main factor leading to the accumulation of amyloid-β and tau proteins, which are also pathological features of AD. This article also discusses why autophagy is indispensable in the early to mature stages of neuronal development and how damage to the function of autophagy can cause neurodevelopmental abnormalities and neurodegenerative diseases. We also summarized the potential role of oligodendrocytes. We believe that its relationship with lysosomes can provide a new perspective and research direction for future research on neurodegenerative diseases. Autophagy-lysosomal pathway damage is considered to be a key factor in the pathology and diagnosis of multiple sclerosis, but we believe that the challenge associated with its transformation into clinical treatment is enormous. These findings suggest that enhancing or improving autophagy function may be an effective treatment method to alleviate the condition of AD patients, which can provide new strategies for clinical treatment and intervention of AD in the future.
Autophagy is a key lysosome-dependent degradation pathway essential for maintaining cellular homeostasis, particularly in the highly secretory pancreas. This review summarizes recent advances in autophagy, selective autophagy, and vesicle trafficking in pancreatic physiology and disease. We focus on the dual role of autophagy, which can support cellular protection and organelle quality control, but also contribute to pathology when dysregulated. We highlight emerging molecular mechanisms linking autophagy with vesicle trafficking systems, including membrane remodeling, organelle contact sites, and key regulators such as VMP1 and Beclin-1. In addition, we discuss the role of autophagy in pancreatic inflammation and cancer, emphasizing its context-dependent function. Finally, we outline recent translational approaches targeting autophagy-related pathways, including pharmacological and genetic strategies, with potential diagnostic and therapeutic relevance in pancreatic diseases.
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.
Highlights What are the main findings? Macroautophagy and its selective forms play an important, multifaceted and often bidirectional role in the pathogenesis of mitochondrial diseases. The role of autophagy in cellular organelles, apart from mitophagy, has not been sufficiently investigated. What are the implications of the main findings? Restoring autophagy improves mitochondrial function and cell survival in mitochondrial disorders. Studying autophagy in cellular organelles, apart from mitochondria, has the potential to reveal new mechanisms underlying the cellular pathogenesis of mitochondrial diseases and to find new promising approaches to treatment. Abstract Mitochondrial diseases are a heterogeneous group of inherited disorders caused by defects in the mitochondrial genome or nuclear genes encoding proteins essential for mitochondrial function. These conditions are characterised by progressive dysfunction of tissues with high energy demands, particularly the nervous and muscular systems. In recent years, increasing consideration has been paid to the role of autophagy—the cellular mechanism for the degradation and recycling of intracellular components in the pathogenesis of mitochondrial diseases. This review synthesizes current knowledge on molecular mechanisms of macroautophagy and selective forms of au-tophagy targeting specific organelles and structures: mitophagy, pexophagy, ribophagy, ER-phagy, aggrephagy, lipophagy, lisophagy, and nucleophagy. Using classic mitochondrial syndromes—Kearns–Sayre syndrome (KSS), MERRF, and MELAS, as well as various mitochondrial myopathies—as examples, we discuss experimental evidence indicating both compensatory activation of autophagy and its insufficiency or blockade at different stages. Furthermore, we examine the link between deficiencies of key fatty acid β-oxidation enzymes (VLCAD, MCAD, CPT2) and impaired autophagic flux, including secondary defects of mitophagy mediated by energy deficiency. The review systematises current understanding of how dysregulation of selective autophagy promotes the accumulation of damaged mitochondria, oxidative stress, inflammation, and cell death in mitochondrial diseases. Prospects for therapeutic modulation of autophagy as a potential approach to treating these disorders are discussed.
Autophagy is an evolutionarily conserved cellular quality control pathway that responds to the metabolic state of the cell, and its dysregulation has been broadly associated with metabolic disorders like diabetes mellitus. Among different types of autophagy, mitophagy or the selective autophagic clearance of dysfunctional mitochondria has emerged as particularly relevant in pancreatic β-cell biology and its pathophysiology. Recent advances in functional genomics and animal studies implicate the autophagy/mitophagy pathway components as effector transcripts at diabetes risk loci, providing a new rationale for investigation of genetic determinants of autophagy/mitophagy in β cells. In this review, we take a β-cell centric perspective to examine the evidence for autophagy/mitophagy across four clinically relevant diabetes categories (type 1, type 2, gestational, and monogenic diabetes) and discuss the functional significance and complexity of these pathways in β-cell failure.
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