Exploiting Multi-Omics Profiling and Systems Biology to Investigate Functions of TOMM34

Although modern biology is now in the post-genomic era with vastly increased access to high-quality data, the set of human genes with a known function remains far from complete. This is especially true for hundreds of mitochondria-associated genes, which are under-characterized and lack clear functional annotation. However, with the advent of multi-omics profiling methods coupled with systems biology algorithms, the cellular role of many such genes can be elucidated. Here, we report genes and pathways associated with TOMM34, Translocase of Outer Mitochondrial Membrane, which plays role in the mitochondrial protein import as a part of cytosolic complex together with Hsp70/Hsp90 and is upregulated in various cancers. We identified genes, proteins, and metabolites altered in TOMM34^-/- HepG2 cells. To our knowledge, this is the first attempt to study the functional capacity of TOMM34 using a multi-omics strategy. We demonstrate that TOMM34 affects various processes including oxidative phosphorylation, citric acid cycle, metabolism of purine, and several amino acids. Besides the analysis of already known pathways, we utilized de novo network enrichment algorithm to extract novel perturbed subnetworks, thus obtaining evidence that TOMM34 potentially plays role in several other cellular processes, including NOTCH-, MAPK-, and STAT3-signaling. Collectively, our findings provide new insights into TOMM34's cellular functions.