Aug 2026· Antioxidants· Vol 15, pp. 1043· 0 citations· 41 references
Medicine
TL;DR
Findings support a model in which MCU-1-dependent elevation of [Ca2+]mito contributes to oxidative mitochondrial defects in PDR-1/Parkin-deficient muscle.
Abstract
Parkinson’s disease (PD) is widely regarded as a disorder of dopaminergic neurons that involves mitochondrial dysfunction, impaired mitophagy, and oxidative stress. However, the nature and significance of skeletal muscle pathology remain unclear. In this study, we used Caenorhabditis elegans, which lack muscle stem cells in adulthood, to examine the effects of PDR-1/Parkin deficiency on mitochondrial homeostasis and motor function under conditions where muscle regeneration does not occur. Silencing of pdr-1 attenuated age-related mitochondrial fragmentation in body-wall muscle cells but was associated with later impairments in locomotor activity and loss of nuclear GFP signals, suggesting progressive muscle cell damage. By day 2 of adulthood, mitochondrial reactive oxygen species (mtROS) levels were elevated in muscle cells subjected to pdr-1 RNAi, and in the pdr-1(gk448) mutant this mtROS elevation was accompanied by a reduction in mitochondrial membrane potential (ΔΨm). In vivo imaging further revealed elevated mitochondrial Ca2+ levels ([Ca2+]mito) in PDR-1-deficient muscle cells. Moreover, the mtROS increase associated with PDR-1 deficiency was suppressed in mcu-1 mutants. These findings support a model in which MCU-1-dependent elevation of [Ca2+]mito contributes to oxidative mitochondrial defects in PDR-1/Parkin-deficient muscle.
BACKGROUND
Mitochondrial dysfunction and neuroinflammation drive dopaminergic neuron loss in Parkinson's disease (PD). While BMSC-derived small extracellular vesicles (BMSC-Exo) are neuroprotective, their ability to repair mitochondrial deficits is limited. We engineered mitochondrial-enriched sEVs (Exo-Mito) to evaluate their effects on microglia-neuron interactions in a PD-relevant model.
METHODS
BMSC-Exo-Mito were characterized via TEM, NTA, and immunoblotting. Their therapeutic efficacy was assessed using an MPP + -induced BV2/SH-SY5Y transwell co-culture model. Assessments included ROS levels, mitochondrial membrane potential, ATP quantification, mitophagy flux, and signaling pathway analysis.
RESULTS
Exo-Mito significantly restored mitochondrial homeostasis by reducing ROS, preserving membrane potential, and increasing ATP production. Mechanistically, Exo-Mito enhanced PINK1/Parkin-dependent mitophagy and PGC-1alpha/TFAM-mediated biogenesis. In BV2 microglia, Exo-Mito suppressed the NF-kappaB/NLRP3 axis, reduced proinflammatory cytokines, and promoted M2 polarization. In SH-SY5Y cells with dopaminergic phenotype, Exo-Mito was associated with reactivated PI3K/Akt/mTOR signaling, preserved tyrosine hydroxylase expression, and inhibited apoptosis. Functionally, Exo-Mito improved SH-SY5Y cell and restored microglial migratory capacity, showing superior efficacy to unmodified BMSC-Exo.
CONCLUSION
Mitochondria-enriched BMSC sEVs protect SH-SY5Y cells by coordinating mitochondrial quality control and modulating neuroinflammation. These findings support Exo-Mito as a promising cell-free therapeutic strategy for Parkinson's disease.
Shanshan Shi, Ruyue Liu, Chang Liu et al.· Brain Research· 0 citations
DJ-1 is a redox-sensitive protein implicated in early-onset Parkinson’s disease, and its mitochondrial localization protects against oxidative stress, but the mechanisms regulating its submitochondrial targeting and functional impact on mitochondrial integrity remain poorly understood. We identify voltage-dependent anion channel 1 (VDAC1) as a regulator of the submitochondrial distribution of DJ-1 during stress. Endogenous DJ-1 interacted with VDAC1, and loss of VDAC1 reduced stress-induced DJ-1 accumulation within the mitochondrial matrix. VDAC1-deficient neurons exhibited mitochondrial fragmentation, impaired oxidative phosphorylation, reduced ATP levels, altered reactive oxygen species (ROS) responses, and increased sensitivity to MPP⁺. Matrix-targeted, but not outer-membrane-targeted, DJ-1 rescued basal, ATP-linked, and maximal respiration, improved mitochondrial morphology, and enhanced neuronal survival. ATP synthase inhibition also rapidly increased mitochondrial DJ-1, suggesting bioenergetic stress promotes its mitochondrial accumulation. Our findings identify compartment-specific localization as a key determinant of DJ-1 function and establish VDAC1-dependent matrix targeting as a critical mechanism supporting mitochondrial integrity during stress.
Jéssica Taday, D. Im, S. Hewitt et al.· bioRxiv· 0 citations
Mitochondrial NAD+ homeostasis, sustained by the inner membrane transporter MCART1, is critical for oxidative metabolism and stress resilience. Inhibition of complex I by 1-methyl-4-phenylpyridinium (MPP+) triggers metabolic collapse and mitochondrial dysfunction, yet whether MCART1 provides a protective gatekeeping function against the MPP+ toxin remains unclear. Here, we show that loss of MCART1 exacerbates mitochondrial dysfunction under physiological conditions, and that MCART1 contributes to maintaining membrane potential, preventing ATP depletion, and suppressing ROS accumulation in MPP+-treated neuronal cells. We identify key NAD+-binding residues within the predicted substrate-binding pocket. Mutation of these residues uncouples MPP+ resistance from constitutive NAD+ transport, defining a structural determinant required for the stress-responsive gatekeeping function of MCART1. These findings establish that MCART1 acts as a conditionally indispensable protector of mitochondrial integrity during complex I poisoning, and reveal that failure of this NAD+ influx pathway drives metabolic collapse in the MPP+ toxin model relevant to Parkinson's disease.
Simple Summary Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to progressive muscle weakness and severe muscle wasting. In addition to neuronal loss, increasing evidence suggests that problems in mitochondrial function, the process by which cells produce energy, may contribute to disease development and progression. In this study, we investigated the effects of Mdivi-1, a drug that inhibits mitochondrial fragmentation, in a mouse model of ALS. Treatment began before symptoms appeared in order to assess whether it could slow disease progression. Our findings showed that Mdivi-1 partially protected motor neurones in the spinal cord, but this did not result in improved motor performance. Moreover, treated animals developed more severe muscle wasting and changes in muscle fiber composition. We also observed cellular alterations associated with impaired neuromuscular function. Overall, these results highlight that mitochondrial dynamics play a complex and context-dependent role in the disease. A better understanding of these mechanisms will be important for developing more effective therapeutic strategies for ALS.
Maria Ciuro, Chantal Rovetto, Angela A. Sirna et al.· Biology· 0 citations
Mitochondrial dysfunction underlies the major defect in muscle atrophy (characterized by the loss of skeletal muscle mass and function). Mesenchymal stem cells (MSCs), which can mediate mitochondrial transfer (MT) via tunneling nanotubes (TNTs), have been shown to exert therapeutic effects, yet the underlying mechanism remains unclear. Mitochondrial Rho GTPase 1 (Miro1) is crucial for regulating mitochondrial homeostasis; in this study, we aimed to investigate the roles of Miro1 and Milton in MSC-based therapy for muscle atrophy. Dexamethasone (DEX)-induced C2C12 cells and chronically aged mice were used as in vitro cellular and in vivo muscle atrophy models, respectively. In vitro experiments demonstrated that overexpression of Milton alone failed to enhance MT in DEX-induced C2C12 cells. Although Milton could promote the formation of TNTs, it was unable to drive mitochondrial movement along microtubules in the absence of Miro1.In contrast, Miro1 knockdown (MSCmiro1Lo) significantly reduced MT in vivo, while Miro1 overexpression (MSCmiro1Hi) improved mitochondrial morphology, increased muscle fiber count and cross-sectional area, upregulated the expression of type I/III collagen, and downregulated the expression of Atrogin1 and MURF1. Additionally, Miro1 overexpression ameliorated functional outcomes such as grip strength, running distance, and physical activity, and elevated the levels of proteins related to mitochondrial fusion, mitophagy, and biogenesis in damaged muscle cells. These findings indicate that Miro1 is a critical driver of MT, and Miro1-enhanced MT confers substantial in vivo therapeutic benefits. This study provides robust evidence supporting Miro1 as a potential target for the treatment of muscle atrophy-related disorders.
Fangling Zhao, Jin Fu, Linli Gao et al.· Stem cell research & therape...· 0 citations
Astrocyte-specific mitochondrial dysfunctions and calcium dysregulation are identified as key features of LRRK2- and PRKN-related pathology, providing new insights into how glial metabolic alterations contribute to neurodegeneration in PD.
Giovanna C. Cavalcante, Camille C. Caldeira da Silva, É. Vogt et al.· bioRxiv· 0 citations
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