Altered Transcriptional Profile of Mitochondrial DNA-Encoded OXPHOS Subunits, Mitochondria Quality Control Genes, and Intracellular ATP Levels in Blood Samples of Patients with Parkinson’s Disease

Article type: Research Article

Authors: Gezen-Ak, Duygu^a | Alaylıoğlu, Merve^a | Genç, Gençer^b | Şengül, Büşra^a | Keskin, Ebru^a | Sordu, Pelin^a | Güleç, Zeynep Ece Kaya^c | Apaydın, Hülya^c | Bayram-Gürel, Çiğdem^a | Ulutin, Turgut^a | Yılmazer, Selma^d | Ertan, Sibel^{e; *} | Dursun, Erdinç^{a; f; *}

Affiliations: [a] Department of Medical Biology, Brain and Neurodegenerative Disorders Research Laboratories, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey | [b] Department of Neurology, Şişli Etfal Training and Research Hospital, Istanbul, Turkey | [c] Department of Neurology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey | [d] Department of Medical Biology, Faculty of Medicine, Altınbaş University, Istanbul, Turkey | [e] Department of Neurology, Faculty of Medicine, Koç University, Istanbul, Turkey | [f] Department of Neuroscience, Institute of Neurological Sciences, Istanbul University-Cerrahpasa, Istanbul, Turkey

Correspondence: [*] Correspondence to: Erdinç Dursun and Sibel Ertan, Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, 34098, Istanbul, Turkey. Tel.: +90 212 414 30 00/22032/ +90 533 339 98 82; Fax: +90 212 414 30 42; E-mails: [email protected], [email protected].

Abstract: Mitochondrial dysfunctions are significant contributors to neurodegeneration. One result or a cause of mitochondrial dysfunction might be the disruption of mtDNA transcription. Limited data indicated an altered expression of mtDNA encoded transcripts in Alzheimer’s disease (AD) or Parkinson’s disease (PD). The number of mitochondria is high in cells with a high energy demand, such as muscle or nerve cells. AD or PD involves increased risk of cardiomyopathy, suggesting that mitochondrial dysfunction might be systemic. If it is systemic, we should observe it in different cell types. Given that, we wanted to investigate any disruption in the regulation of mtDNA encoded gene expression in addition to PINK1, PARKIN, and ATP levels in peripheral blood samples of PD cases who are affected by a neurodegenerative disorder that is very well known by its mitochondrial aspects. Our results showed for the first time that: 1) age of onset > 50 PD sporadic (PDS) cases: mtDNA transcription and quality control genes were affected; 2) age of onset <50 PDS cases: only mtDNA transcription was affected; and 3) PD cases with familial background: only quality control genes were affected. mtDNA copy number was not a confounder. Intracellular ATP levels of PD case subgroups were significantly higher than those of healthy subjects. We suggest that a systemic dysregulation of transcription of mtDNA or mitochondrial quality control genes might result in the development of a sporadic form of the disease. Additionally, ATP elevation might be an independent compensatory and response mechanism. Hyperactive cells in AD and PD require further investigation.

Keywords: Alzheimer’s disease, ATP, mitochondrial DNA, OXPHOS, PARKIN, Parkinson’s disease, PINK1

DOI: 10.3233/JAD-191164

Journal: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 287-307, 2020