@article{932f66770c914d7eab09f4da2c5274a7,
title = "Noncanonical role of singleminded-2s in mitochondrial respiratory chain formation in breast cancer",
abstract = "Dysregulation of cellular metabolism is a hallmark of breast cancer progression and is associated with metastasis and therapeutic resistance. Here, we show that the breast tumor suppressor gene SIM2 promotes mitochondrial oxidative phosphorylation (OXPHOS) using breast cancer cell line models. Mechanistically, we found that SIM2s functions not as a transcription factor but localizes to mitochondria and directly interacts with the mitochondrial respiratory chain (MRC) to facilitate functional supercomplex (SC) formation. Loss of SIM2s expression disrupts SC formation through destabilization of MRC Complex III, leading to inhibition of electron transport, although Complex I (CI) activity is retained. A metabolomic analysis showed that knockout of SIM2s leads to a compensatory increase in ATP production through glycolysis and accelerated glutamine-driven TCA cycle production of NADH, creating a favorable environment for high cell proliferation. Our findings indicate that SIM2s is a novel stabilizing factor required for SC assembly, providing insight into the impact of the MRC on metabolic adaptation and breast cancer progression.",
author = "Wall, {Steven W.} and Lilia Sanchez and Tuttle, {Kelly Scribner} and Pearson, {Scott J.} and Shivatheja Soma and Wyatt, {Garhett L.} and Carter, {Hannah N.} and Jenschke, {Ramsey M.} and Lin Tan and Martinez, {Sara A.} and Lorenzi, {Philip L.} and Gohil, {Vishal M.} and Monique Rijnkels and Porter, {Weston W.}",
note = "Funding Information: This work was supported by NIH grants R01HD102149A1, R01HD083952-01, S10OD012304-01, P30CA016672, 1S10RR025111-01, R01GM111672, and P30ES029067. This work was also supported by The Welch Foundation Grant, A1810, TAMU X-Grant, MitoX: Targeting Mitochondria in Human Health. Facilities used can be found at RRID:SCR_021637 and RRID: SCR_022479. This work was also funded by R01HD102149A1 (W.W.P.), R01HD083952-01 (W.W.P., M.R.), R01GM111672 (V.M.G.), The Welch Foundation Grant (A-1810) (V.M.G.), and MitoX: Targeting Mitochondria in Human Health (W.W.P., M.R., V.M.G.). Funding Information: We acknowledge Dr. Erin Giles for the use of her laboratory to perform Seahorse analysis, the Metabolomics Core Facility at MD Anderson supported by NIH grants S10OD012304-01 and P30CA016672, University of Texas Health Science Center at San Antonio Institutional Mass Spectrometry Laboratory funded in part by NIH grant 1S10RR025111-01 for the purchase of the Orbitrap mass spectrometer (S.T. Weintraub) and expert technical assistance of Sammy Pardo and Dana Molleur for mass spectrometry analyses, the Integrated Microscopy and Imaging Laboratory at Texas A&M College of Medicine (RRID:SCR_021637), and the Texas A&M Image Analysis Laboratory (RRID: SCR_022479) funded by P30 ES029067. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = may,
doi = "10.1038/s12276-023-00996-0",
language = "English (US)",
volume = "55",
pages = "1046--1063",
journal = "Experimental and Molecular Medicine",
issn = "1226-3613",
publisher = "Korean Society of Med. Biochemistry and Mol. Biology",
number = "5",
}