UC Berkeley

Translocase of outer mitochondrial membrane 40 (TOMM40, aka TOM40) is the major channel-forming subunit of the translocase of outer mitochondrial membrane (TOM) complex that regulate mitochondrial function by importing nuclear-encoded proteins. TOMM40 is located at mitochondria-endoplasmic reticulum contact sites (MERCs), which play a key role in cellular signaling, with known effects on mitochondria bioenergetics and lipid synthesis. Furthermore, we have used RNA-seq to assess global transcriptional response to statin exposure in immortalized lymphoblastoid cell lines (LCLs) derived from participants in a clinical trial who were treated with 40mg/day of simvastatin for 6 weeks. Our previous studies using this model system identified a number of novel genes affecting cholesterol metabolism and in vivo statin LDL (low-density lipoprotein) cholesterol response, including TOMM40.

Statins are the drugs most commonly used for lowering plasma LDL cholesterol and cardiovascular disease risk. Although generally well tolerated, statins can induce myopathy, a major cause of non-adherence to treatment. Cellular studies have identified statin-induced myopathy to be associated with impaired mitochondrial function and morphology. In Chapter 2, we show that TOMM40 and TOMM22 play a key role in mediating statin-induced mitochondrial dysfunction as well as disruption of mitochondrial dynamics in skeletal myotubes. These findings suggest a novel mechanism by which adverse effects of statin treatment on mitochondrial dynamics that may contribute to the development of statin-induced myopathy are mediated by reduced TOMM40 and TOMM22 gene expression.

Beyond the mitochondria, we explore the role of TOMM40 on regulation of lipid metabolism via MERCs. Fundamentally, the gene encoding TOMM40 is adjacent to that for APOE, a protein with central functions in lipid and lipoprotein transport. Recent GWAS studies have shown that a number of SNPs in linkage disequilibrium between these two genes are significantly associated with plasma lipid levels. While these associations have generally been attributed to APOE, no previous studies have addressed the possibility that TOMM40 has an independent effect on lipid metabolism. In Chapter 3, our investigation of molecular mechanisms underlying the effects of TOMM40 knockdown on lipid metabolism has revealed a number of novel findings, including a key role for the LXR transcription factor due both to transcriptional upregulation and increased activation by oxysterols that are generated by mitochondria-induced reactive oxygen species. Interestingly, the increased LXR activity also results in reduced intracellular cholesterol via both upregulation of the membrane cholesterol transporter ABCA1 and increased production and secretion of oxysterol-derived cholic acid. Finally, and importantly, we have shown using a number of experimental approaches that the LXR-mediated effects described above result from disruption of mitochondria-ER contact sites (MERCs), where TOMM40 plays a key role, and that lipid droplet contact sites are consequently shifted from the ER to mitochondria.

Overall, these findings demonstrate TOMM40 plays a key role in connecting mitochondrial function and lipid metabolism.