Underappreciated Roles of the Translocase of the Outer and Inner Mitochondrial Membrane Protein Complexes in Human Disease

Mitochondria are critical for cellular survival, and for their proper functioning, translocation of ∼1500 proteins across the mitochondrial membranes is required. The translocase of the outer (TOMM) and inner mitochondrial membrane (TIMM) complexes are major components of this translocation machinery. Through specific processes, preproteins and other molecules are imported, translocated, and directed to specific mitochondrial compartments for their function. In this study, we review the association of subunits of these complexes with human disease. Pathogenic mutations have been identified in the TIMM8A (DDP) and DNAJC19 (TIMM14) genes and are linked to Mohr-Tranebjærg syndrome and dilated cardiomyopathy syndrome (with and without ataxia), respectively. Polymorphisms in TOMM40 have been associated with Alzheimer's disease, frontotemporal lobar degeneration, Parkinson's disease with dementia, dementia with Lewy bodies, nonpathological cognitive aging, and various cardiovascular-related traits. Furthermore, reduced protein expression levels of several complex subunits have been associated with Parkinson's disease, Meniere's disease, and cardiovascular disorders. However, increased mRNA and protein levels of complex subunits are found in cancers. This review highlights the importance of the mitochondrial import machinery in human disease and stresses the need for further studies. Ultimately, this knowledge may prove to be critical for the development of therapeutic modalities for these conditions.