Mitochondria-targeted oligomeric α-synuclein induces TOM40 degradation and mitochondrial dysfunction in Parkinson's disease and parkinsonism-dementia of Guam.

Autor: Vasquez V; Division of DNA Repair Research, Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA.; Neuroscience Center, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología, (INDICASAT AIP), Panama City, Panama., Kodavati M; Division of DNA Repair Research, Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA., Mitra J; Division of DNA Repair Research, Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA., Vedula I; Center for Bioenergetics, Houston Methodist Research Institute, Houston, TX, USA., Hamilton DJ; Center for Bioenergetics, Houston Methodist Research Institute, Houston, TX, USA.; Department of Medicine, Houston Methodist, Weill Cornell Medicine affiliate, Houston, TX, USA., Garruto RM; Departments of Anthropology and Biological Sciences, Binghamton University, State University of New York, Binghamton, NY, USA., Rao KS; Department of Biotechnology, KLEF Deemed to be University, Vaddeswaram, India., Hegde ML; Division of DNA Repair Research, Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA. mlhegde@houstonmethodist.org.; Department of Neuroscience, Weill Cornell Medical College, New York, NY, USA. mlhegde@houstonmethodist.org.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 Dec 18; Vol. 15 (12), pp. 914. Date of Electronic Publication: 2024 Dec 18.
DOI: 10.1038/s41419-024-07258-5
Abstrakt: Mitochondrial dysfunction is a central aspect of Parkinson's disease (PD) pathology, yet the underlying mechanisms are not fully understood. This study investigates the link between α-Synuclein (α-Syn) pathology and the loss of translocase of the outer mitochondrial membrane 40 (TOM40), unraveling its implications for mitochondrial dysfunctions in neurons. We discovered that TOM40 protein depletion occurs in the brains of patients with Guam Parkinsonism-Dementia (Guam PD) and cultured neurons expressing α-Syn proteinopathy, notably, without corresponding changes in TOM40 mRNA levels. Cultured neurons expressing α-Syn mutants, with or without a mitochondria-targeting signal (MTS) underscores the role of α-Syn's mitochondrial localization in inducing TOM40 degradation. PDe-related etiological factors, such as 6-hydroxydopamine or ROS/metal ions stress, which promotes α-Syn oligomerization, exacerbate TOM40 depletion in PD patient-derived cells with SNCA gene triplication. Although α-Syn interacts with both TOM40 and TOM20 in the outer mitochondrial membrane, degradation is selective for TOM40, which occurs via the ubiquitin-proteasome system (UPS) pathway. Our comprehensive analyses using Seahorse technology, mitochondrial DNA sequencing, and damage assessments, demonstrate that mutant α-Syn-induced TOM40 loss results in mitochondrial dysfunction, characterized by reduced membrane potential, accumulation of mtDNA damage, deletion/insertion mutations, and altered oxygen consumption rates. Notably, ectopic supplementation of TOM40 or reducing pathological forms of α-Syn using ADP-ribosylation inhibitors ameliorate these mitochondrial defects, suggesting potential therapeutic avenues. In conclusion, our findings provide crucial mechanistic insights into how α-Syn accumulation leads to TOM40 degradation and mitochondrial dysfunction, offering insights for targeted interventions to alleviate mitochondrial defects in PD.
Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: Human postmortem brain tissue from Guam PD, Guam ALS, and age-matched Guam non-neurological controls were sourced from the Binghamton Biorepository Archive (ALS-Guam). These samples were obtained as de-identified frozen specimens. The studies involving human samples were conducted in accordance with the ethics board standards at the Binghamton Biorepository Archive (ALS-Guam) and the institutional review boards at the Houston Methodist Research Institute (protocol IBC00001560). Additionally, experiments involving non-neurological control and PD patient-derived neural progenitor cells (hNPSCs) were approved by the institutional review boards at the Houston Methodist Research Institute (protocol IBC00001560).
(© 2024. The Author(s).)
Databáze: MEDLINE
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