Venkatesan, DhivyaIyer, MahalaxmiNarayanasamy, ArulGopalakrishnan, Abilash ValsalaVellingiri, Balachandar2024-01-212024-08-132024-01-212024-08-132023-07-31893764810.1007/s12035-023-03500-xhttps://kr.cup.edu.in/handle/32116/3870Parkinson�s disease (PD) is an advancing age-associated progressive brain disorder which has various diverse factors, among them mitochondrial dysfunction involves in dopaminergic (DA) degeneration. Aging causes a rise in mitochondrial abnormalities which leads to structural and functional modifications in neuronal activity and cell death in PD. This ends in deterioration of mitochondrial function, mitochondrial alterations, mitochondrial DNA copy number (mtDNA CN) and oxidative phosphorylation (OXPHOS) capacity. mtDNA levels or mtDNA CN in PD have reported that mtDNA depletion would be a predisposing factor in PD pathogenesis. To maintain the mtDNA levels, therapeutic approaches have been focused on mitochondrial biogenesis in PD. The depletion of mtDNA levels in PD can be influenced by autophagic dysregulation, apoptosis, neuroinflammation, oxidative stress, sirtuins, and calcium homeostasis. The current review describes the regulation of mtDNA levels and discusses the plausible molecular pathways in mtDNA CN depletion in PD pathogenesis. We conclude by suggesting further research on mtDNA depletion which might show a promising effect in predicting and diagnosing PD. � 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.en-USCopy numberMitochondrial DNAMolecular pathwaysParkinson�s diseaseTFAMTherapeutic strategiesReviewhttps://link.springer.com/10.1007/s12035-023-03500-x