Assistant Professor of Cell Biology, Development and PhysiologyLab Homepage: https://www.thelewislab.org/
Mitochondria perform a diverse set of fundamental functions in eukaryotic cells, including ATP production via respiration, amino acid synthesis and cellular ion and phospholipid homeostasis. Collectively, the many mitochondria within each cell form a dynamic network that spans the cytoplasm and is responsive to metabolic signals and energy demands on the micron scale. Defective mitochondria cause metabolic and neurodegenerative diseases, thus understanding how mitochondrial networks integrate signals to tune the functions of an individual mitochondrion to subcellular cues is a major unresolved problem in the field of organelle biology. An essential aspect of disease etiology and progression is how mitochondrial networks coordinate the regulation of their unique, polyploid genome - mitochondrial DNA. However, the determinants of cellular mtDNA abundance, distribution and gene expression remain poorly understood. In my laboratory, we are dissecting the membrane remodeling events that distribute mtDNA within organelle networks; identifying the constituents of regulatory mitochondrial DNA-protein complexes; and investigating how the surprisingly asymmetric inheritance of mtDNA and its cytoplasmic distribution may subfunctionalize individual mitochondria towards or away from respiration. Using this integrated approach, we are determining how mtDNA maintenance and membrane dynamics specify mitochondrial subtypes to meet local demands.
Subramanian K, Jochem A, Le Vasseur M, Lewis SC, Paulson BR, Reddy TR, Russell JD, Coon JJ, Pagliarini DJ, and JM Nunnari. Coenzyme Q biosynthetic proteins assemble in a substrate-dependent manner into domains at ER-mitochondria contacts. J Cell Biol, Jan 2019, jcb.201808044; DOI: 10.1083/jcb.201808044.
Mallat A, Uchiyama LF, Lewis SC, Fredenburg RA, Terada Y, Ji N, Nunnari J, Tseng C. (2018) Discovery and characterization of selective small molecule inhibitors of the mammalian mitochondrial division dynamin DRP1. BBRC, Mar 27, pii: S0006-291X(18)30711-3.
Lewis SC, Uchiyama LF and J Nunnari. (2016) ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells. Science, 353(6296): aaf5549. doi: 10.1126/science.aaf5549.
Lewis SC, Joers P, Willcox S, Griffith JD, Jacobs HT, Hyman BC. (2015) A rolling-circle replication mechanism produces multimeric lariats of mitochondrial DNA in Caenorhabditis elegans. PLoS Genetics, 11(2): e1004985.
Joers P, Lewis SC, Fukuoh A, Parhiala M, Ellila S, Holt IJ, Jacobs HT. (2013) Mitochondrial transcription terminator family members mTTF and mTerf5 have opposing roles in coordination of mtDNA synthesis. PLoS Genetics 9(9): e1003800.
Denver DR, Dolan P, Wilhelm LJ, Sung W, Lucas-Lledó JI, Howe DK, Lewis SC, Okamoto K, Thomas WK, Lynch M, Baer CF. (2009) A genome-wide view of Caenorhabditis elegans base-substitution mutation processes. PNAS 106 (38):16310-4.
Last Updated 2023-01-29