Impaired complex-I mitochondrial biogenesis in Parkinson disease frontal cortex.
Parkinson's disease (PD) can include a progressive frontal lobe α-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-1α 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-1α 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.
Parkinson's Disease Research Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
Ravindar R
RR
Thomas
Paula M
PM
Keeney
James P
JP
Bennett
D044944:Acyl-CoA Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000648:ultrastructure; D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005625:Frontal Lobe / Q000473:pathology* / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D046228:Microarray Analysis; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D063269:Mitochondrial Turnover / Q000502:physiology*; D058953:Neural Stem Cells; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000473:pathology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012402:Rotenone / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004268:DNA-Binding Proteins; D035683:MicroRNAs; D024101:Mitochondrial Proteins; C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C499631:TFAM protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D012402:Rotenone; D044944:Acyl-CoA Dehydrogenases; C549517:ACAD9 protein, human; D042967:Electron Transport Complex I