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Background <p>Mitochondrial dysfunction is increasingly recognized as a central pathogenic mechanism in Parkinson’s disease (PD). Among mitochondrial components, mitochondrial DNA (mtDNA) has emerged as a critical determinant of neuronal vulnerability. This systematic review synthesizes current evidence on the role of mtDNA alterations in PD pathogenesis and highlights emerging therapeutic approaches that target mitochondrial genome stability.</p> Methods <p>Following PRISMA 2020 guidelines, a comprehensive search of PubMed, Scopus, and Web of Science databases was performed from inception to October 2025. Studies investigating mtDNA mutations, deletions, copy number variation, oxidative damage, and associated molecular pathways in PD were included. Quality assessment was conducted using the Newcastle–Ottawa Scale for human studies and the ToxRTool for experimental studies.</p> Results <p>Out of 3202 retrieved records, 33 studies met inclusion criteria. Evidence converged across four thematic domains: (1) genetic alterations in mtDNA, including point mutations, deletions, and haplogroup-specific susceptibilities that impair oxidative phosphorylation and increase oxidative stress; (2) toxin-induced mtDNA damage, whereby MPTP, MPP⁺, and rotenone trigger <span>d</span>-loop destabilization, copy number loss, and site-specific lesions; (3) altered mitochondrial dynamics and quality control, involving dysregulation of PGC-1α, TFAM, and MTERF proteins; and (4) therapeutic strategies, such as salvianolic acid B, VEGF73-101, Rhapontigenin, Nrf2 activation, mitochondrial gene therapy (MTD–TFAM), and cGAS–STING pathway modulation, which restored mitochondrial bioenergetics and reduced neuroinflammation in preclinical models.</p> Conclusions <p>MtDNA alterations—encompassing structural mutations, oxidative injury, and regulatory imbalance—represent a unifying mechanism linking genetic predisposition, environmental toxins, and cellular stress in PD. While evidence supports mtDNA instability as a driver of neurodegeneration, clinical translation remains limited. Future research should integrate haplogroup analysis, longitudinal mtDNA monitoring, and mtDNA-targeted interventions to enable precision mitochondrial therapeutics for Parkinson’s disease.</p>

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Mitochondrial DNA as a key player in Parkinson’s disease: a systematic review of pathogenic pathways and emerging therapeutic approaches

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月28日

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  • Shiva Mohammad Aminzadeh,
  • Maedeh Khatami,
  • Seyedeh Mona Aghamirzaei,
  • Seyedeh Asrin Seyedoshohadaei,
  • Arash Pooladi,
  • Ramyar Rahimi Darehbagh

摘要

Background

Mitochondrial dysfunction is increasingly recognized as a central pathogenic mechanism in Parkinson’s disease (PD). Among mitochondrial components, mitochondrial DNA (mtDNA) has emerged as a critical determinant of neuronal vulnerability. This systematic review synthesizes current evidence on the role of mtDNA alterations in PD pathogenesis and highlights emerging therapeutic approaches that target mitochondrial genome stability.

Methods

Following PRISMA 2020 guidelines, a comprehensive search of PubMed, Scopus, and Web of Science databases was performed from inception to October 2025. Studies investigating mtDNA mutations, deletions, copy number variation, oxidative damage, and associated molecular pathways in PD were included. Quality assessment was conducted using the Newcastle–Ottawa Scale for human studies and the ToxRTool for experimental studies.

Results

Out of 3202 retrieved records, 33 studies met inclusion criteria. Evidence converged across four thematic domains: (1) genetic alterations in mtDNA, including point mutations, deletions, and haplogroup-specific susceptibilities that impair oxidative phosphorylation and increase oxidative stress; (2) toxin-induced mtDNA damage, whereby MPTP, MPP⁺, and rotenone trigger d-loop destabilization, copy number loss, and site-specific lesions; (3) altered mitochondrial dynamics and quality control, involving dysregulation of PGC-1α, TFAM, and MTERF proteins; and (4) therapeutic strategies, such as salvianolic acid B, VEGF73-101, Rhapontigenin, Nrf2 activation, mitochondrial gene therapy (MTD–TFAM), and cGAS–STING pathway modulation, which restored mitochondrial bioenergetics and reduced neuroinflammation in preclinical models.

Conclusions

MtDNA alterations—encompassing structural mutations, oxidative injury, and regulatory imbalance—represent a unifying mechanism linking genetic predisposition, environmental toxins, and cellular stress in PD. While evidence supports mtDNA instability as a driver of neurodegeneration, clinical translation remains limited. Future research should integrate haplogroup analysis, longitudinal mtDNA monitoring, and mtDNA-targeted interventions to enable precision mitochondrial therapeutics for Parkinson’s disease.