Impaired Complex-I Mitochondrial Biogenesis in Parkinson Disease Frontal Cortex

Abstract

Parkinson's disease (PD) can include a progressive frontal lobe ␣-synucleinopathy with disability from cognitive decline and cortico-limbic dysregulation that may arise from bioenergetic impairments. We examined in PD frontal cortex regulation of mitochondrial biogenesis (mitobiogenesis) and its effects on Complex-I. We quantified expression of 33 nuclear genome (nDNA)-encoded and 7 mitochondrial genome (mtDNA)-encoded Complex-I genes, 6 Complex-I assembly factors and multiple mitobiogenesis genes. We related these findings to levels of Complex-I proteins and NADH-driven electron flow in mitochondria from these same specimens reported in earlier studies. We found widespread, decreased expression of nDNA Complex-I genes that correlated in some cases with mitochondrial Complex-I protein levels, and of ACAD9, a Complex-I assembly factor. mtDNA-transcribed Complex-I genes showed ∼ constant expression within each PD sample but variable expression across PD samples that correlated with NRF1. Relationships among PGC-1␣ and its downstream targets NRF1 and TFAM were very similar in PD and CTL and were related to mitochondrial NADH-driven electron flow. MicroRNA arrays revealed multiple miRNA's regulated >2-fold predicted to interact with PGC-1␣ or its upstream regulators. Exposure of cultured human neurons to NO, rotenone and TNF-alpha partially reproduced mitobiogenesis down-regulation. In PD frontal cortex mitobiogenesis signaling relationships are maintained but down-regulated, correlate with impaired mitochondrial NADH-driven electron flow and may arise from combinations of nitrosative/oxidative stresses, inflammatory cytokines, altered levels of mitobiogenesis gene-interacting microRNA's, or other unknown mechanisms. Stimulation of mitobiogenesis in PD may inhibit rostral disease progression and appearance of secondary symptoms referable to frontal cortex.

Mitochondrial activity in the frontal cortex area 8 and angular gyrus in Parkinson's disease and Parkinson's disease with dementia

“…However, these alterations have only a moderate impact on the activity of mitochondrial complexes, as only complex III activity is reduced in the frontal cortex and angular gyrus in PD. These changes do not contradict the marked impairment of mitochondria biogenesis, altered mRNA expression, deregulation of several microRNAs predicted to interact with complex I regulators, and alterations of protein levels which also occur in frontal cortex in PD (43). Rather, they are consistent with a scenario in which several molecules, including mitochondrial membrane proteins, ion channels and mitochondrial subunits, are altered to determinate thresholds until they produce altered activity.…”

Mitochondrial Quality Control in Neurodegenerative Diseases: Focus on Parkinson's Disease and Huntington's Disease

“…Important advances emphasizing the contribution of impaired mitochondrial biogenesis to PD have recently been made. For downregulation of nuclear-encoded complex I genes was found associated with decreased expression of mitobiogenesis factors in PD frontal cortex, pointing at defects in mitochondrial biogenesis as another player in mitochondrial dysfunction (Thomas et al, 2012 ). Parkin also plays a role in the mitochondrial biogenesis pathway through the ubiquitination of Parkin Interacting Substrate (PARIS), leading to its ubiquitin-dependent degradation.…”

Mitochondria and Calcium Regulation as Basis of Neurodegeneration Associated With Aging

“…Interestingly, it has been shown that CypD knock-out mice exhibit delayed axonal degeneration, a common feature of diverse neurodegenerative diseases ( Barrientos et al, 2011 ; Catenaccio et al, 2017 ; Salvadores et al, 2017 ). Indeed, genetic deletion of CypD delays disease progression in other mouse models of neurodegenerative disorders, including ALS ( Martin et al, 2009 ), PD ( Thomas et al, 2012 ), and multiple sclerosis ( Forte et al, 2007 ). Therefore, novel compounds that inhibit mPTP opening are currently been developed, including sanglifehrin A, N-Me-Ala-6-cyclosporin A, and antmanide ( Rao et al, 2014 ).…”