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Introduction: Mitochondrial dysfunction is a cause and/or consequence of aging and neurodegenerative disorders. Mitochondria and peroxisomes are tightly connected organelles that cooperate with each other in the oxidation of lipids and maintenance of redox homeostasis. However, the peroxisomechr('39')s role in the modulation of the mitochondrial regulatory factors has remained unanswered. SIRT1- PGC-1α interaction as a pivotal pathway in energy expenditure leads to mitochondrial biogenesis. HDAC6 and HDAC10 also regulate mitochondrial dynamics. Methods: In this study, to disturb peroxisome matrix protein import, PEX5 was downregulated in rat dorsal hippocampus by lentivirus-mediated shRNA. The impact of PEX5 downregulation on peroxisomes was explored by measuring catalase activity as a regular peroxisome matrix enzyme, and PMP70 and PEX14 expression. After that, the level of factors involved in mitochondrial biogenesis PGC-1α, and its downstream transcription factor TFAM were measured by qPCR. Mitochondrial-related HDACs, SIRT1, SIRT3, HDAC6, and HDAC10, were measured by western blotting. Besides, spatial learning and memory were assessed using the Morris Water Maze task. Results: Our results revealed a significant reduction of HDAC6 and SIRT1, alongside with decrease in both mitochondrial biogenesis factors PGC-1α and TFAM, and no alteration in HDAC10 and SIRT3. Despite all observed changes, memory performance displayed no detectable alteration in the experimental groups. These data suggest the role of peroxisomes in modulating mitochondrial dynamics via regulation of HDAC6 and SIRT1 expression. Conclusion: Therefore, peroxisome dysfunctions may occur upstream to mitochondrial failure and can be considered as a potential therapeutic target for aging and age-related disorders.
Types of Manuscript: Original Research | Subject: Others

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