Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

Abstract

The majority of proteins localised to mitochondria are encoded by the nuclear genome, with approximately 1500 proteins imported into mammalian mitochondria. Dysfunction in this fundamental cellular process is linked to a variety of pathologies including neuropathies, cardiovascular disorders, myopathies, neurodegenerative diseases and cancer, demonstrating the importance of mitochondrial protein import machinery for cellular function. Correct import of proteins into mitochondria requires the co‐ordinated activity of multimeric protein translocation and sorting machineries located in both the outer and inner mitochondrial membranes, directing the imported proteins to the destined mitochondrial compartment. This dynamic process maintains cellular homeostasis, and its dysregulation significantly affects cellular signalling pathways and metabolism. This review summarises current knowledge of the mammalian mitochondrial import machinery and the pathological consequences of mutation of its components. In addition, we will discuss the role of mitochondrial import in cancer, and our current understanding of the role of mitochondrial import in neurodegenerative diseases including Alzheimer's disease, Huntington's disease and Parkinson's disease.

Organelle Crosstalk Regulators Are Regulated in Diseases, Tumors, and Regulatory T Cells: Novel Classification of Organelle Crosstalk Regulators

“…We also found that TOMM40 was upregulated in 14 out of 33 types of cancers (42.4%) ( Supplementary Figure 13B ). Our results are well-correlated with previous reports that TOMM40 (TOM40) and significant numbers of MT protein import machineries overexpressed in cancers such as the TOM complex (TOM20, TOM40, TOM7, and TOM70), TIM23 complex, TIM22 complex, small Tim chaperons and Mia40, and Tim 44 ( 111 , 114 ). To elucidate the functional aspects of TOMM40, we searched the PPI network database in the STRING database ( https://string-db.org/ ).…”

Multiomics Identification of Potential Targets for Alzheimer Disease and Antrocin as a Therapeutic Candidate

“…Moreover, ATP6V1A maturations were implicated in the onset of developmental encephalopathy with epilepsy, suggesting its role in regulating neuronal development [65]. A clinical study by Dutta et al [66] reported that two patients with de novo mutations (T607I and I554F) in the C-terminus of the TOM70 protein exhibited white matter abnormalities, hypotonia, hyperreflexia, dystonia, and cognitive deficits.…”

Mitochondrial dynamics in health and disease

“…As such, the vast majority of~1200 mitochondrial proteins are nuclear-encoded [3,4]. These proteins are translated via cytosolic ribosomes before being processed and imported into mitochondria through the TIM/TOM system [5]. However, mitochondria also contain a vestigial genome within the matrixin humans, mitochondrial DNA (mtDNA) encodes only 13 polypeptideshighly hydrophobic subunits of the OXPHOS machinery [6].…”