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Tauopathies are a group of progressive neurodegenerative disorders characterized by the presence of insoluble intracellular tau filaments in the brain. Evidence suggests that there is a tight connection between mitochondrial dysfunction and tauopathies, including Alzheimer's disease. However, whether mitochondrial dysfunction occurs prior to the detection of tau aggregates in tauopathies remains elusive. Here, we utilized transgenic nematodes expressing the full length of wild type tau in neuronal cells and monitored mitochondrial morphology alterations over time. Although tau-expressing nematodes did not accumulate detectable levels of tau aggregates during larval stages, they displayed increased mitochondrial damage and locomotion defects compared to the control worms. Chelating calcium restored mitochondrial activity and improved motility in the tau-expressing larvae suggesting a link between mitochondrial damage, calcium homeostasis and neuronal impairment in these animals. Our findings suggest that defective mitochondrial function is an early pathogenic event of tauopathies, taking place before tau aggregation and undermining neuronal homeostasis and organismal fitness. Understanding the molecular mechanisms causing mitochondrial dysfunction early in tauopathy will be of significant clinical and therapeutic value and merits further investigation.

Aging is the major risk factor for several life‐threatening pathologies and impairs the function of multiple cellular compartments and organelles. Age‐dependent deterioration of nuclear morphology is a common feature in evolutionarily divergent organisms. Lipid droplets have been shown to localize in most nuclear compartments, where they impinge on genome architecture and integrity. However, the significance of progressive nuclear lipid accumulation and its impact on organismal homeostasis remain obscure. Here, we implement non‐linear imaging modalities to monitor and quantify age‐dependent nuclear lipid deposition in Caenorhabditis elegans. We find that lipid droplets increasingly accumulate in the nuclear envelope, during aging. Longevity‐promoting interventions, such as low insulin signaling and caloric restriction, abolish the rate of nuclear lipid accrual and decrease the size of lipid droplets. Suppression of lipotoxic lipid accumulation in hypodermal and intestinal nuclei is dependent on the transcription factor HLH‐30/TFEB and the triglyceride lipase ATGL‐1. HLH‐30 regulates the expression of ATGL‐1 to reduce nuclear lipid droplet abundance in response to lifespan‐extending conditions. Notably, ATGL‐1 localizes to the nuclear envelope and moderates lipid content in long‐lived mutant nematodes during aging. Our findings indicate that the reduced ATGL‐1 activity leads to excessive nuclear lipid accumulation, perturbing nuclear homeostasis and undermining organismal physiology, during aging. [ABSTRACT FROM AUTHOR]

Mitochondria are cellular organelles that play an essential role in generating the chemical energy needed for the biochemical reactions in cells. Mitochondrial biogenesis, i.e., de novo mitochondria formation, results in enhanced cellular respiration, metabolic processes, and ATP generation, while autophagic clearance of mitochondria (mitophagy) is required to remove damaged or useless mitochondria. The balance between the opposing processes of mitochondrial biogenesis and mitophagy is highly regulated and crucial for the maintenance of the number and function of mitochondria as well as for the cellular homeostasis and adaptations to metabolic demands and extracellular stimuli. In skeletal muscle, mitochondria are essential for maintaining energy homeostasis, and the mitochondrial network exhibits complex behaviors and undergoes dynamic remodeling in response to various conditions and pathologies characterized by changes in muscle cell structure and metabolism, such as exercise, muscle damage, and myopathies. In particular, the involvement of mitochondrial remodeling in mediating skeletal muscle regeneration following damage has received increased attention, as modifications in mitophagy-related signals arise from exercise, while variations in mitochondrial restructuring pathways can lead to partial regeneration and impaired muscle function. Muscle regeneration (through myogenesis) following exercise-induced damage is characterized by a highly regulated, rapid turnover of poor-functioning mitochondria, permitting the synthesis of better-functioning mitochondria to occur. Nevertheless, essential aspects of mitochondrial remodeling during muscle regeneration remain poorly understood and warrant further characterization. In this review, we focus on the critical role of mitophagy for proper muscle cell regeneration following damage, highlighting the molecular mechanisms of the mitophagy-associated mitochondrial dynamics and network reformation. [ABSTRACT FROM AUTHOR]

Mitochondria are highly dynamic and semi-autonomous organelles, essential for many fundamental cellular processes, including energy production, metabolite synthesis, ion homeostasis, lipid metabolism and initiation of apoptotic cell death. Proper mitochondrial physiology is a prerequisite for health and survival. Generation of new and removal of damaged or unwanted mitochondria are tightly controlled processes that need to be accurately coordinated for the maintenance of mitochondrial and cellular homeostasis. Mitophagy is a conserved, mitochondria-specific autophagic clearance process. An intricate regulatory network balances mitophagy with mitochondrial biogenesis. Proper coordination of these opposing processes is important for stress resistance and longevity. Age-dependent decline of mitophagy both inhibits removal of dysfunctional or superfluous mitochondria and impairs mitochondrial biogenesis resulting in progressive mitochondrial accretion and consequently, deterioration of cell function. Nodal regulatory factors that contribute to mitochondrial homeostasis have been implicated in the pathogenesis of several age-associated pathologies, such as neurodegenerative and cardiovascular disorders and cancer, among others. Thus, mitophagy is emerging as a potential target for therapeutic interventions against diseases associated with ageing. In this review, we survey the molecular mechanisms that govern and interface mitophagy with mitochondrial biogenesis, focusing on key elements that hold promise for the development of pharmacological approaches towards enhancing healthspan and quality of life in the elderly. [ABSTRACT FROM AUTHOR]

Impaired mitochondrial maintenance in disparate cell types is a shared hallmark of many human pathologies and ageing. How mitochondrial biogenesis coordinates with the removal of damaged or superfluous mitochondria to maintain cellular homeostasis is not well understood. Here we show that mitophagy, a selective type of autophagy targeting mitochondria for degradation, interfaces with mitochondrial biogenesis to regulate mitochondrial content and longevity in Caenorhabditis elegans. We find that DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress in C. elegans. Impairment of mitophagy compromises stress resistance and triggers mitochondrial retrograde signalling through the SKN-1 transcription factor that regulates both mitochondrial biogenesis genes and mitophagy by enhancing DCT-1 expression. Our findings reveal a homeostatic feedback loop that integrates metabolic signals to coordinate the biogenesis and turnover of mitochondria. Uncoupling of these two processes during ageing contributes to overproliferation of damaged mitochondria and decline of cellular function. [ABSTRACT FROM AUTHOR]

Abstract: Mitochondria are highly dynamic organelles and their proper function is crucial for the maintenance of cellular homeostasis. Mitochondrial biogenesis and mitophagy are two pathways that regulate mitochondrial content and metabolism preserving homeostasis. The tight regulation between these opposing processes is essential for cellular adaptation in response to cellular metabolic state, stress and other intracellular or environmental signals. Interestingly, imbalance between mitochondrial proliferation and degradation process results in progressive development of numerous pathologic conditions. Here we review recent studies that highlight the intricate interplay between mitochondrial biogenesis and mitophagy, mainly focusing on the molecular mechanisms that govern the coordination of these processes and their involvement in age-related pathologies and ageing. [Copyright &y& Elsevier]

Mitophagy is a conserved, mitochondria-specific autophagic clearance process. We recently discovered an intricate regulatory network that balances mitophagy with mitochondrial biogenesis. Proper coordination of these opposing processes is important for stress resistance and longevity. Nodal regulatory factors that contribute to mitochondrial homeostasis have also been linked to carcinogenesis, highlighting mitophagy as a potential target for therapeutic interventions against cancer. [ABSTRACT FROM AUTHOR]

Mitochondria are highly dynamic and semi-autonomous organelles, essential for many fundamental cellular processes, including energy production, metabolite synthesis and calcium homeostasis, among others. Alterations in mitochondrial activity not only influence individual cell function but also, through non-cell autonomous mechanisms, whole body metabolism, healthspan and lifespan. Energy homeostasis is orchestrated by the complex interplay between mitochondrial biogenesis and mitochondria-selective autophagy (mitophagy). However, the cellular and molecular pathways that coordinate these 2 opposing processes remained obscure. In our recent study, we demonstrate that DCT-1, theCaenorhabditis eleganshomolog of the mammalian BNIP3 and BNIP3L/NIX, is a key mediator of mitophagy, and functions in the same genetic pathway with PINK-1 and PDR-1 (the nematode homologs of PINK1 and Parkin respectively) to promote longevity and prevent cell damage under stress conditions. Interestingly, accumulation of damaged mitochondria activates SKN-1 (SKiNhead-1), the nematode homolog of NRF2, which in turn initiates a compensatory retrograde signaling response that impinges on both mitochondrial biogenesis and removal. In this commentary, we discuss the implications of these new findings in the context of innate immunity and aging. Unraveling the regulatory network that governs the crosstalk between mitochondrial biogenesis and mitophagy will enhance our understanding of the molecular mechanisms that link aberrant energy metabolism to aging and disease. [ABSTRACT FROM AUTHOR]

Mitochondria represent the major bioenergetic hub coordinating cellular and organismal homeostasis. The underlying causes of many pathologies tormenting humans converge on impaired mitochondrial maintenance. Mitochondria-specific autophagy (mitophagy), a cellular catabolic process targeting mitochondria, holds a prominent role in mitochondrial quality control. In addition to core autophagic machinery components, mitophagy exploits a variety of molecules that identify damaged or superfluous mitochondria and mediate their elimination. Signaling pathways integrating environmental and genetic stimuli interact with key mitophagy effectors to activate cellular stress response mechanisms, ultimately modulating health and lifespan. Here, we review the signaling cascades and molecular mechanisms that govern the process of mitophagy and discuss their involvement in ageing and neurodegeneration. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging. [ABSTRACT FROM AUTHOR]