Peroxisome biogenesis factor 5 controlled Histone deacetylase 6 and Situin1 expression and modulatedmitochondrial biogenesis in rat dorsal hippocampus

Mitochondria and peroxisomes are tightly connected organelles that cooperate in lipid oxidation and maintenance of redox homeostasis. However, the peroxisome’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. Histone deacetylase (HDAC)6 and HDAC10 also regulate mitochondrial dynamics. Mitochondrial dysfunction is a cause and/or consequence of aging and neurodegenerative disorders.

In this study, to disturb importing proteins into the peroxisomes, PEX5 was down-regulated in the dorsal hippocampus by lentivirus-mediated shRNA. The impact of PEX5 reduction on peroxisomes was explored by assessment of catalase activity, a regular peroxisome matrix enzyme, and PMP70 and PEX14 expression. Then, mitochondrial biogenesis factors, PGC-1α, and mitochondrial transcription factor A (TFAM) were measured by quantitative polymerase chain reaction and mitochondrial-related HDACs, SIRT1, SIRT3, HDAC6 and HDAC10, by western blotting. Besides, spatial learning and memory were assessed using the Morris water maze task.

Our results revealed a significant reduction of HDAC6 and SIRT1, alongside with decrease in 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.

Peroxisome dysfunctions may occur upstream to mitochondrial failure and can be considered as a potential therapeutic target for aging and age-related disorders.