Mitochondrial Protein Import Dysfunction in Pathogenesis of Neurodegenerative Diseases

Mitochondria play an essential role in maintaining energy homeostasis and cellular survival. In the brain, higher ATP production is required by mature neurons for communication. Most of the mitochondrial proteins transcribe in the nucleus and import in mitochondria through different pathways of the mitochondrial protein import machinery. This machinery plays a crucial role in determining mitochondrial morphology and functions through mitochondrial biogenesis. Failure of this machinery and any alterations during mitochondrial biogenesis underlies neurodegeneration resulting in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD) etc. Current knowledge has revealed the different pathways of mitochondrial protein import machinery such as translocase of the outer mitochondrial membrane complex, the presequence pathway, carrier pathway, β-barrel pathway, and mitochondrial import and assembly machinery etc. In this review, we have discussed the recent studies regarding protein import machinery, beyond the well-known effects of increased oxidative stress and bioenergetics dysfunctions. We have elucidated in detail how these types of machinery help to import and locate the precursor proteins to their specific location inside the mitochondria and play a major role in mitochondrial biogenesis. We further discuss their involvement in mitochondrial dysfunctioning and the induction of toxic aggregates in neurodegenerative diseases like AD and PD. The review supports the importance of import machinery in neuronal functions and its association with toxic aggregated proteins in mitochondrial impairment, suggesting a critical role in fostering and maintaining neurodegeneration and therapeutic response.