Faculty Research Page
Assistant Professor of Cell and Developmental BiologyLab Homepage: https://www.thelewislab.org/
Within each of our cells, the genetic control of metabolism is split between the nuclear genome and thousands of small, circular mitochondrial genomes. The co-regulation of these two genomes is required for aerobic life, yet paradoxically, their replication and inheritance are uncoupled. Defects in mitochondrial DNA cause hereditary metabolic diseases that impact tissues with high energy demand such as the brain, muscle and heart and are also linked to cancer and the innate immune response. We aim to reveal the mechanisms that ensure mtDNA integrity and inheritance in metazoans, using quantitative imaging, genetics and systems biology approaches.
Mitochondrial DNA encodes functional RNAs and proteins that are critical for the synthesis of adenosine triphosphate or ATP - the chemical currency the must be spent for cellular growth or repair. Every animal cell contains many many copies of mtDNA that are replicated asynchronously, without regard for the nuclear cell cycle. How mtDNA replication is regulated is not well understood, though proper mtDNA replication is key to maintaining a characteristic number of mtDNA copies in highly proliferative tissues, like bone marrow or placenta, as well as in post-mitotic tissues, like the brain, where mitochondrial biogenesis and turnover continue.
We are using multiple approaches to reveal the cellular mechanisms of mitochondrial genome integrity and inheritance:
- Developing new imaging-based assays for analyzing the inheritance of mutant and wild type mitochondrial genomes that co-exist within the same cells
- Probing the molecular functions of previously uncharacterized membrane proteins that are required for mitochondrial genome inheritance in humans
- Developing new imaging approaches to investigate how germline mitochondrial dynamics impact mtDNA inheritance in a C. elegans model
- Developing approaches for mitochondrial transgenesis, opening the door to mitochondrial functional genomics and possibly mitochondrial genome editing
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.
Poinar G, Lewis SC, Hagen N, Hyman BC. (2011) Systematic affinity of the sea urchin parasite, Echinomermella matsi. Nematology 13:747-753.
Hyman BC, Lewis SC, Tang S, Wu Z. (2010) Rampant gene rearrangement and haplotype hypervariation among nematode mitochondrial genomes. Genetica 139(5): 611-5.
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.
Lewis SC, Dyal LA, Hilburn CF, Weitz S, Liau WS, Lamunyon CW, Denver DR. (2009) Molecular evolution in Panagrolaimus nematodes: origins of parthenogenesis, hermaphroditism and the Antarctic species P. davidi. BMC Evolutionary Biology 9(1):15.
Last Updated 2019-10-29