Master regulator could be key to controlling cancer progression
An international team of researchers has uncovered the mechanism through which mitochondria meet the changing metabolic needs of the human cell cycle. This study could enable scientists to prevent the progression of cancer.
Mitochondria are a compartment buried within the cells of all humans. In humans (and in all other eukaryotes), existing mitochondria are used as templates to build more mitochondrial mass ahead of each cell division. Each new daughter cell needs to inherit a fair share of mitochondria in order to survive. So too, in response to increased metabolic demand, the cell’s mitochondrial mass is increased through a process called biogenesis.
Mitochondrial biogenesis requires that millions of molecules of up to 1000 different proteins are made by the cell’s protein synthesis machinery, and imported by mitochondria to increase the cell’s overall mitochondrial mass. All proteins imported by mitochondria enter through the translocase of the outer membrane (TOM) complex. A remarkable piece of nanomachinery, the TOM complex is composed of a core formed by either two or three channel subunits (Tom40) and several additional subunits including a master regulator (Tom22).
A team of researchers from the Monash Biomedicine Discovery Institute and Kyoto Sangyo University and Miyazaki University in Japan have published a new study in the journal Molecular Cell. This study demonstrates how and why changes in the architecture of the TOM complex impact core cellular activity including cell-cycle control, metabolic remodeling and programmed cell death.
The team, including former Monash BDI researcher and first author Dr Takuya Shiota, revealed the mechanism through which the TOM complex converts from a two-channel form to a three-channel form. They demonstrated that these distinct forms selectively import sub-sets of the available proteins during distinct phases of the cell cycle, or – in specific conditions – during the programmed cell death. Programmed cell death and cell cycle control are both key elements in the progression of normal cells to cancer.
The Monash BDI team, led by Professor Trevor Lithgow, used the yeast Saccharomyces cerevisiae as the key experimental model for these discoveries.
“We discovered that a mitochondrial protein called ‘VDAC’ acts to distract the master regulator Tom22. VDAC itself controls activation of events in cell death, as well as serving as the main metabolite pore for metabolic remodeling,” Professor Lithgow said.
“In distracting Tom22 away from the TOM complex VDAC regulates the selectivity of the mitochondrial protein entry gate. Much as a bouncer on a nightclub door, the presence or absence of Tom22 dictates which proteins will gain entry through the gate,” he said.
As new and repurposed drugs for cancer treatment are developed, it is essential that researchers and clinicians understand how processes like mitochondrial biogenesis occur through the cancer cell cycle, and how they might impact on (for better or worse) the response of cancerous cell to drug treatment. Just as in cancer, this is also true for treatments to assist immune cells fighting infectious disease.
Current work in the Monash BDI is directed at the controlling mitochondrial activity in cell death (McArthur et al 2018), metabolic reprogramming during fungal infections (Tucey et al 2018) and VDAC-mimicry in multidrug-resistant gonorrhea (Deo et al 2018).
Read the full paper in Molecular Cell titled Porin Associates with Tom22 to Regulate the Mitochondrial Protein Gate Assembly.
About the Monash Biomedicine Discovery Institute Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.