BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis
Abstract
Glycolysis and apoptosis are considered major but independent pathways that are critical for cell survival. The activity of BAD, a pro-apoptotic BCL-2 family member, is regulated by phosphorylation in response to growth/survival factors. Here we undertook a proteomic analysis to assess whether BAD might also participate in mitochondrial physiology. In liver mitochondria, BAD resides in a functional holoenzyme complex together with protein kinase A and protein phosphatase 1 (PP1) catalytic units, Wiskott-Aldrich family member WAVE-1 as an A kinase anchoring protein, and glucokinase (hexokinase IV). BAD is required to assemble the complex in that Bad-deficient hepatocytes lack this complex, resulting in diminished mitochondria-based glucokinase activity and blunted mitochondrial respiration in response to glucose. Glucose deprivation results in dephosphorylation of BAD, and BAD-dependent cell death. Moreover, the phosphorylation status of BAD helps regulate glucokinase activity. Mice deficient for BAD or bearing a non-phosphorylatable BAD(3SA) mutant display abnormal glucose homeostasis including profound defects in glucose tolerance. This combination of proteomics, genetics and physiology indicates an unanticipated role for BAD in integrating pathways of glucose metabolism and apoptosis.
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WAVE1 was identified as a component of a mitochondria-associated complex containing PKA, protein phosphatase-1, the proapoptotic protein BAD and glucokinase in the liver.
“WAVE1 was identified as a component of a mitochondria-associated complex containing PKA, protein phosphatase-1, the proapoptotic protein BAD and glucokinase in the liver81.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [81]
Immunoelectron microscopy revealed WAVE1 localization on the outer membrane of mitochondria.
“Immunoelectron microscopy revealed WAVE1 localization on the outer membrane of mitochondria81.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [81]
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- Authors
- Danial, N. N., Gramm, C. F., Scorrano, L., Zhang, C.-Y., Krauss, S., Ranger, A. M., Robert Datta, S., Greenberg, M. E., Licklider, L. J., Lowell, B. B., Gygi, S. P., & Korsmeyer, S. J.
- Affiliations
- Howard Hughes Medical Institute (US)
- Beth Israel Deaconess Medical Center (US)
- Boston Children's Hospital (US)
- Harvard University (US)
- Corresponding author
- Korsmeyer, Stanley J.
- ORCID
- Venue
- Nature
- Published
- 2003-08
- Volume
- 424
- Issue
- 6951
- Pages
- 952-956
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2090632954
- Cited by
- 705
- References
- 0
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 16 · 2023: 17 · 2022: 17 · 2021: 19 · 2020: 17 · 2019: 21 · 2018: 21 · 2017: 19 · 2016: 33 · 2015: 28 · 2014: 26 · 2013: 35 · 2012: 43
- FWCI
- 17.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- Bad, glucokinase, mitochondrial protein complexes, glycolysis, apoptosis, Bcl-2 family proteins, protein kinase A, protein phosphatase 1, A-kinase anchoring proteins, hepatocytes, glucose metabolism, glucose tolerance, mitochondrial respiration, glucose deprivation, Bad phosphorylation, glucose homeostasis
- MeSH terms
- Animals, Carrier Proteins, Glucokinase, Glucose, Glycolysis, Homeostasis, Mitochondria, Liver, Phosphorylation, Apoptosis, Gene Deletion, Mice, Knockout, Proto-Oncogene Proteins c-bcl-2, Holoenzymes, Proteomics, Macromolecular Substances, bcl-Associated Death Protein, Mice
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