Mitochondria, the power plants of the cell, are important in aging. They are the descendants of symbiotic bacteria and contain their own DNA, separate from that in the cell nucleus. This mitochondrial DNA is just a remnant, however, as over the course of evolutionary time most of its genes have moved to the nucleus. A complex set of mechanisms exists to transport proteins produced in the nucleus back into mitochondria where they are needed, one part of which is the TIM/TOM complex. This paper focuses on one of the proteins involved, TOM40, or TOMM40, and in particular its relationship with mutations known to play a role in one or more neurodegenerative conditions:
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 Alzheimer's, and is the only nuclear- encoded gene identified in genetic studies to date that presumably contributes to Alzheimer's-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 more than ~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. Amyloid precursor protein enters and obstructs the TOM40 pore, inhibiting import of OXPHOS-related proteins and disrupting the mitochondrial redox balance. Other pathogenic proteins, such as amyloid-β 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. Mitochondria underlie many cellular processes and it is not surprising functional and structural mitochondrial defects contribute to the pathogenesis of age-related diseases, including neurodegenerative diseases.