Mitochondrial dysfunction and neurodegenerative proteinopathies: mechanisms and prospects for therapeutic intervention.

Neurodegenerative proteinopathies are a group of pathologically similar, progressive disorders of the nervous system, characterised by structural alterations within and toxic misfolding of susceptible proteins. Oligomerisation of Aβ, tau, α-synuclein and TDP-43 leads to a toxin gain- or loss-of-function contributing to the phenotype observed in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. Misfolded proteins can adversely affect mitochondria, and post-mitotic neurones are especially sensitive to metabolic dysfunction. Misfolded proteins impair mitochondrial dynamics (morphology and trafficking), preventing functional mitochondria reaching the synapse, the primary site of ATP utilisation. Furthermore, a direct association of misfolded proteins with mitochondria may precipitate or augment dysfunctional oxidative phosphorylation and mitochondrial quality control, causing redox dyshomeostasis observed in disease. As such, a significant interest lies in understanding mechanisms of mitochondrial toxicity in neurodegenerative disorders and in dissecting these mechanisms with a view of maintaining mitochondrial homeostasis in disease. Recent advances in understanding mitochondrially controlled cell death pathways and elucidating the mitochondrial permeability pore bioarchitecture are beginning to present new avenues to target neurodegeneration. Novel mitochondrial roles of deubiquitinating enzymes are coming to light and present an opportunity for a new class of proteins to target therapeutically with the aim of promoting mitophagy and the ubiquitin-proteasome system. The brain is enormously metabolically active, placing a large emphasis on maintaining ATP supply. Therefore, identifying mechanisms to sustain mitochondrial function may represent a common intervention point across all proteinopathies.