Mitochondria in the pathophysiology of Alzheimer's and Parkinson's diseases.
Mitochondria are responsible for the majority of energy production in energy-intensive tissues like brain, modulate Ca+2signaling and control initiation of cell death. Because of their extensive use of oxygen and lack of protective histone proteins, mitochondria are vulnerable to oxidative stress (ROS)-induced damage to their genome (mtDNA), respiratory chain proteins and ROS repair enzymes. Animal and cell models of PD use toxins that impair mitochondrial complex I activity. Maintenance of mitochondrial mass, mitochondrial biogenesis (mitobiogenesis), particularly in high-energy brain, occurs through complex signaling pathways involving the upstream "master regulator" PGC-1alpha that is transcriptionally and post-translationally regulated. Alzheimer disease (AD) and Parkinson disease (PD) brains have reduced respiratory capacity and impaired mitobiogenesis, which could result in beta-amyloid plaques and neurofibrillary tangles. Aggregated proteins in genetic and familial AD and PD brains impair mitochondrial function, and mitochondrial dysfunction is involved in activated neuroinflammation. Mitochondrial ROS can activate signaling pathways that mediate cell death in neurodegenerative diseases. The available data support restoration of mitochondrial function to reduce disease progression and restore lost neuronal function in AD and PD.
Gencia Biotechnology, 706 B Forest St, Charlottesville, VA 22903 USA, ionyango@genciabiotech.com.
Isaac G
IG
Onyango
Gencia Biotechnology, 706 B Forest St, Charlottesville, VA 22903 USA.
Shaharyar M
SM
Khan
Neurodegeneration Therapeutics, 3050 A Berkmar Dr, Charlottesville, VA 22901.
James P
JP
Bennett
D000544:Alzheimer Disease / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D008928:Mitochondria / Q000502:physiology*; D063306:Mitophagy; D009154:Mutation; D001678:Organelle Biogenesis; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000503:physiopathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D002118:Calcium