Noncanonical role of singleminded-2s in mitochondrial respiratory chain formation in breast cancer.

May 01, 2023

Experts: Steven W Wall,Lilia Sanchez,Kelly Scribner Tuttle,Scott J Pearson,Shivatheja Soma,Garhett L Wyatt,Hannah N Carter,Ramsey M Jenschke,Lin Tan,Sara A Martinez,Philip L Lorenzi,Vishal M Gohil,Monique Rijnkels,Weston W Porter

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.
© 2023. The Author(s).

Author

admin

View all posts

ABOUT THE EXPERTS

Steven W Wall,Lilia Sanchez,Kelly Scribner Tuttle,Scott J Pearson,Shivatheja Soma,Garhett L Wyatt,Hannah N Carter,Ramsey M Jenschke,Lin Tan,Sara A Martinez,Philip L Lorenzi,Vishal M Gohil,Monique Rijnkels,Weston W Porter

Steven W Wall

Department of Veterinary Physiology and Pharmacology, School of Veterinary Medicine, Texas A&M University, College Station, TX, 77843, USA.

Lilia Sanchez

Department of Veterinary Physiology and Pharmacology, School of Veterinary Medicine, Texas A&M University, College Station, TX, 77843, USA.

Kelly Scribner Tuttle

Center for Toxicology and Environmental Health, North Little Rock, AR, 72118, USA.

Scott J Pearson

Department of Veterinary Physiology and Pharmacology, School of Veterinary Medicine, Texas A&M University, College Station, TX, 77843, USA.

Shivatheja Soma

Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX, 77843, USA.

Garhett L Wyatt

Department of Veterinary Physiology and Pharmacology, School of Veterinary Medicine, Texas A&M University, College Station, TX, 77843, USA.

Hannah N Carter

Department of Veterinary Physiology and Pharmacology, School of Veterinary Medicine, Texas A&M University, College Station, TX, 77843, USA.

Ramsey M Jenschke

Department of Veterinary Physiology and Pharmacology, School of Veterinary Medicine, Texas A&M University, College Station, TX, 77843, USA.

Lin Tan

Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.

Sara A Martinez

Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.

Philip L Lorenzi

Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.

Vishal M Gohil

Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX, 77843, USA.

Monique Rijnkels

Department of Veterinary Integrative Biosciences, School of Veterinary Medicine, Texas A&M University, College Station, TX, 77843, USA.

Weston W Porter

Department of Veterinary Physiology and Pharmacology, School of Veterinary Medicine, Texas A&M University, College Station, TX, 77843, USA. wporter@tamu.edu.