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Cellular energy metabolism and the core apoptotic pathway are two major determinants of cellular survival. Growth and survival factors stimulate glycolysis and inhibit apoptosis. Consequently, growth factor withdrawal leads to metabolic decline marked by decreased glycolytic rate, lowered oxygen consumption, decreased ATP levels, and reduced protein synthesis. If not reversed, these metabolic changes ultimately lead to apoptosis. The BCL-2 family of proteins, which consists of both death agonists and antagonists, constitutes a critical control point in apoptosis residing immediately upstream to irreversible cellular damage, where family members control the release of apoptogenic factors from mitochondria. Consistent with their ability to control cellular survival, select BCL-2 family members have been shown to function as oncoproteins and tumor suppressors. Although these proteins are best known for their control of apoptosis, recent findings point to novel roles for multiple family members, including their involvement in normal mitochondrial physiology. Mitochondrial dysfunction - such as aberrations in the tricarboxylic acid (TCA) cycle and deficiencies in aerobic fuel metabolism - has been reported in select disease settings, including certain types of cancer and diabetes. The significance of cellular metabolism in cancer has long been recognized; furthermore, it has been noted that patients with diabetes exhibit a higher incidence of cancer, which raises the issue of whether aberrations in glucose homeostasis lead to tumor growth. The molecular underpinnings of these observations, however, have not been fully explored. We have conducted a large-scale proteomic analysis of liver mitochondrial complexes containing BCL-2 family proteins which revealed that BAD, one family member, resides in a large mitochondrial protein complex containing glucokinase (GK, hexokinase IV). Genetic tests further revealed that BAD may function both as a specialized apoptotic "sentinel" responding to abnormalities in glucose metabolism and as an integral regulator embedded in pathways of glucose sensing and utilization. We recently found that BAD impacts cellular bioenergetics by regulating the efficiency with which mitochondria metabolize glucose to generate ATP. Strikingly, both the apoptotic and the metabolic functions of BAD are governed by a common protein domain. We are actively investigating the molecular mechanisms and the intracellular milieu that determine which function of BAD predominates. The long-term goal of this line of investigation is to gain insight into whether the propensity of BAD to impact cellular metabolism and fuel utilization by mitochondria plays any role in tumorigenesis and to explore whether manipulating cellular bioenergetics could have therapeutic benefits.

Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA. EMBO J. 2023 Mar 14; e111901.
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MCL-1 is a master regulator of cancer dependency on fatty acid oxidation. Cell Rep. 2022 10 04; 41(1):111445.
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Mitochondrial pyruvate supports lymphoma proliferation by fueling a glutamate pyruvate transaminase 2-dependent glutaminolysis pathway. Sci Adv. 2022 Sep 30; 8(39):eabq0117.
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Glucose metabolism and pyruvate carboxylase enhance glutathione synthesis and restrict oxidative stress in pancreatic islets. Cell Rep. 2021 11 23; 37(8):110037.
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More Metabolism! Mol Cell. 2021 09 16; 81(18):3659-3664.
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BAD regulates mammary gland morphogenesis by 4E-BP1-mediated control of localized translation in mouse and human models. Nat Commun. 2021 05 19; 12(1):2939.
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UCP1 governs liver extracellular succinate and inflammatory pathogenesis. Nat Metab. 2021 05; 3(5):604-617.
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Development of a novel fluorescent biosensor for dynamic monitoring of metabolic methionine redox status in cells and tissues. Biosens Bioelectron. 2021 Apr 15; 178:113031.
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CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice. Sci Transl Med. 2020 08 26; 12(558).
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Hydrocarbon-Stitched Peptide Agonists of Glucagon-Like Peptide-1 Receptor. ACS Chem Biol. 2020 06 19; 15(6):1340-1348.
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Glucose-dependent partitioning of arginine to the urea cycle protects ß-cells from inflammation. Nat Metab. 2020 05; 2(5):432-446.
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Partitioning of MLX-Family Transcription Factors to Lipid Droplets Regulates Metabolic Gene Expression. Mol Cell. 2020 03 19; 77(6):1251-1264.e9.
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Fibroblastic reticular cells enhance T cell metabolism and survival via epigenetic remodeling. Nat Immunol. 2019 12; 20(12):1668-1680.
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HCF-1 Regulates De Novo Lipogenesis through a Nutrient-Sensitive Complex with ChREBP. Mol Cell. 2019 07 25; 75(2):357-371.e7.
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Grasping for aspartate in tumour metabolism. Nat Cell Biol. 2018 07; 20(7):738-739.
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BAD and KATP channels regulate neuron excitability and epileptiform activity. Elife. 2018 01 25; 7.
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BAD knockout provides metabolic seizure resistance in a genetic model of epilepsy with sudden unexplained death in epilepsy. Epilepsia. 2018 01; 59(1):e1-e4.
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Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets. Cell Death Differ. 2017 02; 24(2):251-262.
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Regulation of mitochondrial nutrient and energy metabolism by BCL-2 family proteins. Trends Endocrinol Metab. 2015 Apr; 26(4):165-75.
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Phospho-BAD BH3 mimicry protects ß cells and restores functional ß cell mass in diabetes. Cell Rep. 2015 Feb 03; 10(4):497-504.
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Measurement of mitochondrial oxygen consumption rates in mouse primary neurons and astrocytes. Methods Mol Biol. 2015; 1241:59-69.
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Adipsin is an adipokine that improves ß cell function in diabetes. Cell. 2014 Jul 03; 158(1):41-53.
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Inhibiting Tankyrases sensitizes KRAS-mutant cancer cells to MEK inhibitors via FGFR2 feedback signaling. Cancer Res. 2014 Jun 15; 74(12):3294-305.
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D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice. Genes Dev. 2014 Mar 01; 28(5):479-90.
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Regulation of hepatic energy metabolism and gluconeogenesis by BAD. Cell Metab. 2014 Feb 04; 19(2):272-84.
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A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators. Nat Struct Mol Biol. 2014 Jan; 21(1):36-42.
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Changing appetites: the adaptive advantages of fuel choice. Trends Cell Biol. 2014 Feb; 24(2):118-27.
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How does the ketogenic diet work? Four potential mechanisms. J Child Neurol. 2013 Aug; 28(8):1027-33.
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Behavioral stress accelerates prostate cancer development in mice. J Clin Invest. 2013 Feb; 123(2):874-86.
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Inactivation of BAD by IKK inhibits TNFa-induced apoptosis independently of NF-?B activation. Cell. 2013 Jan 17; 152(1-2):304-15.
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Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts. Nature. 2012 Nov 22; 491(7425):608-12.
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Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell. 2012 Oct 16; 22(4):547-60.
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Control of tumor bioenergetics and survival stress signaling by mitochondrial HSP90s. Cancer Cell. 2012 Sep 11; 22(3):331-44.
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Polysome profiling in liver identifies dynamic regulation of endoplasmic reticulum translatome by obesity and fasting. PLoS Genet. 2012 Aug; 8(8):e1002902.
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BAD-dependent regulation of fuel metabolism and K(ATP) channel activity confers resistance to epileptic seizures. Neuron. 2012 May 24; 74(4):719-30.
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BAD modulates counterregulatory responses to hypoglycemia and protective glucoprivic feeding. PLoS One. 2011; 6(12):e28016.
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A peptidomics strategy to elucidate the proteolytic pathways that inactivate peptide hormones. Biochemistry. 2011 Mar 29; 50(12):2213-22.
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Noxa: a sweet twist to survival and more. Mol Cell. 2010 Dec 10; 40(5):687-8.
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Fast kinase domain-containing protein 3 is a mitochondrial protein essential for cellular respiration. Biochem Biophys Res Commun. 2010 Oct 22; 401(3):440-6.
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Homeostatic functions of BCL-2 proteins beyond apoptosis. Adv Exp Med Biol. 2010; 687:1-32.
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Bad targets the permeability transition pore independent of Bax or Bak to switch between Ca2+-dependent cell survival and death. Mol Cell. 2009 Feb 13; 33(3):377-88.
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BAD: undertaker by night, candyman by day. Oncogene. 2008 Dec; 27 Suppl 1:S53-70.
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Transplacental exposure to the vacuolar-ATPase inhibitor bafilomycin disrupts survival signaling in beta cells and delays neonatal remodeling of the endocrine pancreas. Exp Toxicol Pathol. 2008 Aug; 60(4-5):295-306.
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Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat Med. 2008 Feb; 14(2):144-53.
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Targeting the cell death-survival equation. Clin Cancer Res. 2007 Dec 15; 13(24):7250-3.
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BCL-2 family proteins: critical checkpoints of apoptotic cell death. Clin Cancer Res. 2007 Dec 15; 13(24):7254-63.
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beta-Cell mitochondria exhibit membrane potential heterogeneity that can be altered by stimulatory or toxic fuel levels. Diabetes. 2007 Oct; 56(10):2569-78.
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Loss of Mcl-1 protein and inhibition of electron transport chain together induce anoxic cell death. Mol Cell Biol. 2007 Feb; 27(4):1222-35.
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OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell. 2006 Jul 14; 126(1):177-89.
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Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci U S A. 2005 Aug 23; 102(34):12005-10.
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v-Abl signaling disrupts SOCS-1 function in transformed pre-B cells. Mol Cell. 2004 Aug 13; 15(3):329-41.
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Cell death: critical control points. Cell. 2004 Jan 23; 116(2):205-19.
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BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature. 2003 Aug 21; 424(6951):952-6.
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Bad-deficient mice develop diffuse large B cell lymphoma. Proc Natl Acad Sci U S A. 2003 Aug 05; 100(16):9324-9.
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Functional involvement of Akt signaling downstream of Jak1 in v-Abl-induced activation of hematopoietic cells. Blood. 2002 Aug 01; 100(3):966-73.
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Positive regulation of interleukin-4-mediated proliferation by the SH2-containing inositol-5'-phosphatase. J Biol Chem. 2000 Sep 22; 275(38):29275-82.
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JAK-STAT signaling activated by Abl oncogenes. Oncogene. 2000 May 15; 19(21):2523-31.
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A thrombopoietin receptor mutant deficient in Jak-STAT activation mediates proliferation but not differentiation in UT-7 cells. Blood. 1999 Oct 15; 94(8):2676-85.
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Transcriptional repression of Stat6-dependent interleukin-4-induced genes by BCL-6: specific regulation of iepsilon transcription and immunoglobulin E switching. Mol Cell Biol. 1999 Oct; 19(10):7264-75.
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Direct interaction of Jak1 and v-Abl is required for v-Abl-induced activation of STATs and proliferation. Mol Cell Biol. 1998 Nov; 18(11):6795-804.
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The thrombopoietin receptor can mediate proliferation without activation of the Jak-STAT pathway. J Exp Med. 1997 Dec 15; 186(12):1947-55.
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Jak-STAT signaling induced by the v-abl oncogene. Science. 1995 Sep 29; 269(5232):1875-7.
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