Mitochondria are double-membrane-bound organelles that are essential for cellular energy production. A fundamental question in eukaryotic cell biology is how the biogenesis of mitochondria is achieved and regulated

Mitochondria are key parts of the cell whose central role is to produce energy in a suitable form for many biological processes. They are also involved in programmed cell death, and in maintaining appropriate levels of calcium in cells. These activities require mitochondria to communicate with the cell nucleus. Disruption of mitochondrial function can lead to a broad range of human diseases including diabetes, neurodegenerative disorders, obesity, cancer and premature ageing. Therefore, a full understanding of the basic processes in mitochondria is needed to identify the causes and consequences of mitochondrial malfunction and to enable us to design new therapies that compensate for or correct such faults. This programme will study how mitochondria are made and how their function responds to the changing requirements of the cell during growth and development.

Mitochondria are double-membrane-bound organelles that are essential for cellular energy production. A fundamental question in eukaryotic cell biology is how the biogenesis of mitochondria is achieved and regulated. The process requires the targeting, import and assembly of over 1500 proteins encoded in nuclear DNA. Because mitochondria also contain their own DNA (mtDNA), which in human contributes 13 key components of the energy production apparatus, bidirectional communication between the nucleus and the mitochondria is essential to produce the desired mitochondrial activity. Our knowledge of nucleus to mitochondria (anterograde) signalling pathways coordinating mitochondrial biogenesis is expanding rapidly, and is known to involve the actions of three factors: AMP kinase, Sirt1 and PGC1a. In contrast, the characterization of the key mitochondrial factors that contribute to the regulation of biogenesis, as well as factors involved in the retrograde response (signalling from mitochondria to the nucleus) is much more limited.

Recently my group has discovered a mitochondrial protein, MPV17, with the intrinsic capacity to stimulate mitochondrial function. MPV17 is an inner mitochondrial membrane protein of unknown function, which belongs to a small family of conserved proteins. In 2006, the identification of MPV17 as the gene responsible for a form of mitochondrial DNA depletion syndrome (MDS) linked its protein product to mtDNA maintenance in vivo. Mitochondrial DNA defects were established as a cause of human disease 25 years ago, and yet there is still much that remains obscure about mtDNA maintenance. In animals and plants almost nothing is known about the anchoring, segregation or transmission of mtDNA. Furthermore, mitochondrial (DNA) dysfunction is also implicated in several common disorders, such as neurodegenerative disease, metabolic syndrome and obesity. Thus the functional characterization of proteins causing mitochondrial disease, such as MPV17, is critical to a full understanding of the role of mitochondria in human health, and the design of rational therapeutic strategies. An ability to stimulate mitochondrial biogenesis is widely recognised as the best immediate prospect for treating mitochondrial dysfunction. Hence, the new finding of MPV17’s effect on mitochondrial biogenesis provides a major new target for this approach, which will be best exploited with knowledge of its mechanism of action.

The plan is to elucidate MPV17’s mechanism of action by dissecting the protein and its partners, studying its pathological variants and the regulation of MPV17 gene expression. Specific aims are: 1) To determine the functional and physiological impacts of MPV17 ablation and mutation via proteomic and metabolite profiling of mutant cell lines and an Mpv17 knockout mouse. Fibroblast deficient cell lines, DG75 mutant and a knockout mouse model for MPV17 are already providing us with material for analysis, and they will be used in the future for transcriptomic, proteomic and metabolomic analyses, and for interventions designed to ameliorate its loss. 2) To characterize MPV17’s protein partners by affinity purification and use truncated forms of the protein to identify the key elements needed for these protein-protein interactions. 3) To dissect the stimulatory effects of MPV17 on mitochondrial biogenesis via metabolic, proteomic, and ultrastructure analyses.

Our studies of MPV17 have led to the realization that the metabolic conditions for cell growth have a major impact on mitochondrial function. We have identified nutrient growth regimes that stimulate mitochondrial protein synthesis while repressing protein synthesis in the cytosol. Therefore we predict that some mechanisms of stimulating mitochondrial capacity will repress cytosolic protein synthesis and thereby arrest cell growth and division.