Previously, we have shown that a heteroplasmic mutation in mitochondrial DNA-encoded complex I ND5 subunit gene resulted in an enhanced tumorigenesis through increased resistance to apoptosis. Here we report that the tumorigenic phenotype associated with complex I dysfunction could be reversed by introducing a yeast NADH quinone oxidoreductase (NDI1) gene. The NDI1 mediated electron transfer from NADH to Co-Q, bypassed the defective complex I and restored oxidative phosphorylation in the host cells. Alternatively, suppression of complex I activity by a specific inhibitor, rotenone or induction of oxidative stress by paraquat led to an increase in the phosphorylation of v-AKT murine thymoma viral oncogene (AKT) and enhanced the tumorigenesis. On the other hand, antioxidant treatment can ameliorate the reactive oxygen species-mediated AKT activation and reverse the tumorigenicity of complex I-deficient cells. Our results suggest that complex I defects could promote tumorigenesis through induction of oxidative stress and activation of AKT pathway.

Translation of mRNAs is tightly regulated and constantly surveyed for errors. Aberrant translation can trigger co-translational protein and RNA quality control processes, impairments of which cause neurodegeneration by still poorly understood mechanism(s). Here we show that quality control of translation of mitochondrial outer membrane (MOM)-localized mRNA intersects with the turnover of damaged mitochondria, both orchestrated by the mitochondrial kinase PINK1. Mitochondrial damage causes stalled translation of complex-I 30 kDa subunit (C-I30) mRNA on MOM, triggering the recruitment of co-translational quality control factors Pelo, ABCE1, and NOT4 to the ribosome/mRNA-ribonucleoprotein complex. Damage-induced ubiquitination of ABCE1 by NOT4 generates poly-ubiquitin signals that attract autophagy receptors to MOM to initiate mitophagy. In the Drosophila PINK1 model, these factors act synergistically to restore mitophagy and neuromuscular tissue integrity. Thus ribosome-associated co-translational quality control generates an early signal to trigger mitophagy. Our results have broad therapeutic implications for the understanding and treatment of neurodegenerative diseases.

The mitochondrial respiratory chain consists of 5 enzyme complexes that are responsible for ATP generation. The paradigm of the electron transport chain as discrete enzymes diffused in the inner mitochondrial membrane has been replaced by the solid state supercomplex model wherein the respiratory complexes associate with each other to form supramolecular complexes. Defects in these supercomplexes, which have been shown to be functionally active and required for forming stable respiratory complexes, have been associated with many genetic and neurodegenerative disorders demonstrating their biomedical significance. In this review, we will summarize the functional and structural significance of supercomplexes and provide a comprehensive review of their assembly and the assembly factors currently known to play a role in this process.

Defects in Complex I assembly is one of the emerging underlying causes of severe mitochondrial disorders. The assembly of Complex I has been difficult to understand due to its large size, dual genetic control and the number of proteins involved. Mutations in Complex I subunits as well as assembly factors have been reported to hinder its assembly and give rise to a range of mitochondria disorders. In this review, we summarize the recent progress made in understanding the Complex I assembly pathway. In particularly, we focus on the known as well as novel assembly factors and their role in assembly of Complex I and human disease.