The Broad Impact of TOM40 on Neurodegenerative Diseases in Aging

Mitochondrial dysfunction is an important factor in the pathogenesis of age-related diseases, including neurodegenerative diseases like Alzheimer's and Parkinson's spectrum disorders. A polymorphism in Translocase of the Outer Mitochondrial Membrane - 40 kD (TOMM40) is associated with risk and age-of onset of late-onset AD, and is the only nuclear- encoded gene identified in genetic studies to date that presumably contributes to LOAD-related mitochondria dysfunction. In this review, we describe the TOM40-mediated mitochondrial protein import mechanism, and discuss the evidence linking TOM40 with Alzheimer's (AD) and Parkinson's (PD) diseases. All but 36 of the >~1,500 mitochondrial proteins are encoded by the nucleus and are synthesized on cytoplasmic ribosomes, and most of these are imported into mitochondria through the TOM complex, of which TOM40 is the central pore, mediating communication between the cytoplasm and the mitochondrial interior. APP enters and obstructs the TOM40 pore, inhibiting import of OXPHOS-related proteins and disrupting the mitochondrial redox balance. Other pathogenic proteins, such as Aβ and alpha-synuclein, readily pass through the pore and cause toxic effects by directly inhibiting mitochondrial enzymes. Healthy mitochondria normally import and degrade the PD-related protein Pink1, but Pink1 exits mitochondria if the membrane potential collapses and initiates Parkin-mediated mitophagy. Under normal circumstances, this process helps clear dysfunctional mitochondria and contributes to cellular health, but PINK1 mutations associated with PD exit mitochondria with intact membrane potentials, disrupting mitochondrial dynamics, leading to pathology. Thus, TOM40 plays a central role in the mitochondrial dysfunction that underlies age-related neurodegenerative diseases. Learning about the factors that control TOM40 levels and activity, and how TOM40, specifically, and the TOM complex, generally, interacts with potentially pathogenic proteins, will provide deeper insights to AD and PD pathogenesis, and possibly new targets for preventative and/or therapeutic treatments.