Metabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of the mitochondrial tricarboxylic acid (TCA) cycle enzyme subunit succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss of SDHB induces the Warburg effect, triggers dysregulation of [Ca2+]i, and aberrantly activates calpain and protein kinase Cdk5, through conversion of its cofactor from p35 to p25. Consequently, aberrant Cdk5 initiates a phospho-signaling cascade where GSK3 inhibition inactivates energy sensing by AMP kinase through dephosphorylation of the AMP kinase γ subunit, PRKAG2. Overexpression of p25-GFP in mouse adrenal chromaffin cells also elicits this phosphorylation signaling and causes PC. A potent Cdk5 inhibitor, MRT3-007, reverses this phospho-cascade, invoking a senescence-like phenotype. This therapeutic approach halted tumor progression in vivo. Thus, we reveal an important mechanistic feature of metabolic sensing and demonstrate that its dysregulation underlies tumor progression in PC and likely other cancers.

Cell Signaling Technology Danvers MA 01923 USA

Department of Hematology St Jude Children's Research Hospital Memphis TN 38105 USA

Department of Internal Medicine Division of Endocrinology University of Florida College of Medicine and Malcom Randall VA Medical Center Gainesville FL 32608 USA

Department of Medicine Division of Hematology and Oncology University of Florida Gainesville FL 32608 USA

Department of Physiological Sciences College of Veterinary Medicine University of Florida Gainesville FL 32610 USA

Department of Radiology University of Alabama at Birmingham Heersink School of Medicine Birmingham AL 35233 USA

Department of Surgery University of Alabama at Birmingham Heersink School of Medicine Birmingham AL 35233 USA

Department of Surgery University of Alabama at Birmingham Heersink School of Medicine Birmingham AL 35233 USA; O'Neal Comprehensive Cancer Center and the Department of Neurobiology University of Alabama at Birmingham Heersink School of Medicine Birmingham AL 35233 USA

Eppley Institute for Research in Cancer and Allied Diseases University of Nebraska Medical Center Omaha NE 68198 USA

Institute of Biotechnology Czech Academy of Sciences Prague West 252 50 Czech Republic; School of Pharmacy Medical Science Griffith University Southport QLD 4222 Australia

Metabolic Signalling Laboratory St Vincent's Institute of Medical Research Fitzroy VIC Australia; Mary MacKillop Institute for Health Research Australian Catholic University Melbourne VIC Australia

Perha Pharmaceuticals Hôtel de Recherche Perharidy Peninsula 29680 Roscoff France

Section on Medical Neuroendocrinology Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD 20892 USA

UT Health Science Center at Houston Department of Neurology University of Texas McGovern Medical School Houston TX 77030 USA

Komentář v

Nat Rev Endocrinol. 2022 Nov;18(11):656. doi: 10.1038/s41574-022-00744-w. PubMed

Zobrazit více v PubMed

Anderson NM, Mucka P, Kern JG, and Feng H (2018). The emerging role and targetability of the TCA cycle in cancer metabolism. Protein Cell 9, 216–237. 10.1007/s13238-017-0451-1. PubMed DOI PMC

Andrienko TN, Pasdois P, Pereira GC, Ovens MJ, and Halestrap AP (2017). The role of succinate and ROS in reperfusion injury - a critical appraisal. J. Mol. Cell. Cardiol. 110, 1–14. 10.1016/j.yjmcc.2017.06.016. PubMed DOI PMC

Bardella C, Pollard PJ, and Tomlinson I (2011). SDH mutations in cancer. Biochim. Biophys. Acta 1807, 1432–1443. 10.1016/j.bbabio.2011.07.003. PubMed DOI

Barros-Minones L, Martín-de-Saavedra D, Perez-Alvarez S, Orejana L, Suquía V, Goñi-Allo B, Hervias I, López MG, Jordan J, Aguirre N, and Puerta E. (2013). Inhibition of calpain-regulated p35/cdk5 plays a central role in sildenafil-induced protection against chemical hypoxia produced by malonate. Biochim. Biophys. Acta 1832, 705–717. 10.1016/j.bbadis.2013.02.002. PubMed DOI

Baysal BE, and Maher ER (2015). 15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma-paraganglioma syndromes characterized by germline SDHB and SDHD mutations. Endocr Relat Cancer 22, T71–T82. PubMed

Bettayeb K, Baunbæk D, Delehouze C, Loaëc N, Hole AJ, Baumli S, Endicott JA, Douc-Rasy S, Bénard J, Oumata N, et al. (2010). CDK inhibitors roscovitine and CR8 trigger Mcl-1 down-regulation and apoptotic cell death in neuroblastoma cells. Genes Cancer 1, 369–380. 10.1177/1947601910369817. PubMed DOI PMC

Bhuniya D, Umrani D, Dave B, Salunke D, Kukreja G, Gundu J, Naykodi M, Shaikh NS, Shitole P, Kurhade S, et al. (2011). Discovery of a potent and selective small molecule hGPR91 antagonist. Bioorg. Med. Chem. Lett. 21, 3596–3602. 10.1016/j.bmcl.2011.04.091. PubMed DOI

Bibb JA, Snyder GL, Nishi A, Yan Z, Meijer L, Fienberg AA, Tsai LH, Kwon YT, Girault JA, Czernik AJ, et al. (1999). Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 402, 669–671. 10.1038/45251. PubMed DOI

Blank A, Schmitt AM, Korpershoek E, van Nederveen F, Rudolph T, Weber N, Strebel RT, de Krijger R, Komminoth P, and Perren A (2010). SDHB loss predicts malignancy in pheochromocytomas/sympathethic paragangliomas, but not through hypoxia signalling. Endocr. Relat. Cancer 17, 919–928. 10.1677/ERC-09-0316. PubMed DOI

Broekman F, Giovannetti E, and Peters GJ (2011). Tyrosine kinase inhibitors: Multi-targeted or single-targeted? World J. Clin. Oncol. 2, 80–93. 10.5306/wjco.v2.i2.80. PubMed DOI PMC

Buffet A, Venisse A, Nau V, Roncellin I, Boccio V, Le Pottier N, Boussion M, Travers C, Simian C, Burnichon N, et al. (2012). A decade (2001–2010) of genetic testing for pheochromocytoma and paraganglioma. Horm Metab Res 44, 359–366. PubMed

Bujard H (1999). Controlling genes with tetracyclines. J. Gene Med. 1, 372–374. 10.1002/(SICI)1521-2254(199909/10)1:5<372::AID-JGM61>3.0.CO;2-T. PubMed DOI

Cao Y, Bojjireddy N, Kim M, Li T, Zhai P, Nagarajan N, Sadoshima J, Palmiter RD, and Tian R (2017). Activation of gamma2-AMPK suppresses ribosome biogenesis and protects against myocardial ischemia/reperfusion injury. Circ. Res. 121, 1182–1191. 10.1161/CIRCRESAHA.117.311159. PubMed DOI PMC

Carter AM, Tan C, Pozo K, Telange R, Molinaro R, Guo A, De Rosa E, Martinez JO, Zhang S, Kumar N, et al. (2020). Phosphoprotein-based biomarkers as predictors for cancer therapy. Proc. Natl. Acad. Sci. USA 117, 18401–18411. 10.1073/pnas.2010103117. PubMed DOI PMC

Cascon A, Montero-Conde C, Ruiz-Llorente S, Mercadillo F, Letón R, Rodríguez-Antona C, Martínez-Delgado B, Delgado M, Díez A, Rovira A, et al. (2006). Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: a possible hot spot? Genes Chromosomes Cancer 45, 213–219. 10.1002/gcc.20283. PubMed DOI

Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi BVSK, and Varambally S (2017). UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia 19, 649–658. 10.1016/j.neo.2017.05.002. PubMed DOI PMC

Chen J (2016). The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb. Perspect. Med. 6, a026104. 10.1101/cshperspect.a026104. PubMed DOI PMC

Crespo-Biel N, Camins A, Pallàs M, and Canudas AM (2009). Evidence of calpain/cdk5 pathway inhibition by lithium in 3-nitropropionic acid toxicity in vivo and in vitro. Neuropharmacology 56, 422–428. 10.1016/j.neuropharm.2008.09.012. PubMed DOI

Crespo-Biel N, Camins A, Pelegrí C, Vilaplana J, Pallàs M, and Canudas AM. (2007). 3-Nitropropionic acid activates calpain/cdk5 pathway in rat striatum. Neurosci. Lett. 421, 77–81. 10.1016/j.neulet.2007.05.038. PubMed DOI

Cruz JC, Tseng HC, Goldman JA, Shih H, and Tsai LH (2003). Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40, 471–483. 10.1016/s0896-6273(03)00627-5. PubMed DOI

Dahia PL (2014). Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. Nat. Rev. Cancer 14, 108–119. 10.1038/nrc3648. PubMed DOI

Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M, Kung AL, Sanso G, Powers JF, Tischler AS, et al. (2005). A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet. 1, 72–80. 10.1371/journal.pgen.0010008. PubMed DOI PMC

Eijkelenkamp K, Osinga TE, Links TP, and van der Horst-Schrivers ANA (2020). Clinical implications of the oncometabolite succinate in SDHx-mutation carriers. Clin. Genet. 97, 39–53. 10.1111/cge.13553. PubMed DOI PMC

Eisenhofer G, Lenders JW, Linehan WM, Walther MM, Goldstein DS, and Keiser HR (1999). Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. N. Engl. J. Med. 340, 1872–1879. 10.1056/NEJM199906173402404. PubMed DOI

Erba E, Ubezio P, Pepe S, Vaghi M, Marsoni S, Torri W, Mangioni C, Landoni F, and D’Incalci M (1989). Flow cytometric analysis of DNA content in human ovarian cancers. Br. J. Cancer 60, 45–50. 10.1038/bjc.1989.217. PubMed DOI PMC

Erez A, Shchelochkov OA, Plon SE, Scaglia F, and Lee B (2011). Insights into the pathogenesis and treatment of cancer from inborn errors of metabolism. Am. J. Hum. Genet. 88, 402–421. 10.1016/j.ajhg.2011.03.005. PubMed DOI PMC

Evenepoel L, Helaers R, Vroonen L, Aydin S, Hamoir M, Maiter D, Vikkula M, and Persu A (2017). KIF1B and NF1 are the most frequently mutated genes in paraganglioma and pheochromocytoma tumors. Endocr. Relat. Cancer 24, L57–L61. 10.1530/ERC-17-0061. PubMed DOI

Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, Dupuy F, Chambers C, Fuerth BJ, Viollet B, et al. (2013). AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 17, 113–124. 10.1016/j.cmet.2012.12.001. PubMed DOI PMC

Favier J, Brière JJ, Burnichon N, Rivière J, Vescovo L, Benit P, GiscosDouriez I, De Reyniès A, Bertherat J, Badoual C, et al. (2009). The Warburg effect is genetically determined in inherited pheochromocytomas. PLoS One 4, e7094. 10.1371/journal.pone.0007094. PubMed DOI PMC

Fishbein L, Khare S, Wubbenhorst B, DeSloover D, D’Andrea K, Merrill S, Cho NW, Greenberg RA, Else T, Montone K, et al. (2015). Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas. Nat. Commun. 6, 6140. 10.1038/ncomms7140. PubMed DOI PMC

Fliedner SM, Breza J, Kvetnansky R, Powers JF, Tischler AS, Wesley R, Merino M, Lehnert H, and Pacak K (2010). Tyrosine hydroxylase, chromogranin A, and steroidogenic acute regulator as markers for successful separation of human adrenal medulla. Cell Tissue Res. 340, 607–612. 10.1007/s00441-010-0965-9. PubMed DOI PMC

Freund A, Patil CK, and Campisi J (2011). p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 30, 1536–1548. 10.1038/emboj.2011.69. PubMed DOI PMC

Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, et al. (2013). Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1. 10.1126/scisignal.2004088. PubMed DOI PMC

Garcia D, and Shaw RJ (2017). AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol. Cell 66, 789–800. 10.1016/j.molcel.2017.05.032. PubMed DOI PMC

Ge SX, Jung D, and Yao R (2020). ShinyGO: a graphical gene-set enrichment tool for animals and plants. Bioinformatics 36, 2628–2629. 10.1093/bioinformatics/btz931. PubMed DOI PMC

Ghayee HK, Bhagwandin VJ, Stastny V, Click A, Ding LH, Mizrachi D, Zou YS, Chari R, Lam WL, Bachoo RM, et al. (2013). Progenitor cell line (hPheo1) derived from a human pheochromocytoma tumor. PLoS One 8, e65624. 10.1371/journal.pone.0065624. PubMed DOI PMC

Gilissen J, Jouret F, Pirotte B, and Hanson J (2016). Insight into SUCNR1 (GPR91) structure and function. Pharmacol. Ther. 159, 56–65. 10.1016/j.pharmthera.2016.01.008. PubMed DOI

Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, Khau Van Kien P, Corvol P, Plouin PF, and Jeunemaitre X; COMETE Network (2003). Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res. 63, 5615–5621. PubMed

Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Kerlan V, Plouin PF, Rötig A, and Jeunemaitre X (2002). Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. J. Clin. Endocrinol. Metab. 87, 4771–4774. 10.1210/jc.2002-020525. PubMed DOI

Goldstein M, Fuxe K, and Hökfelt T (1972). Characterization and tissue localization of catecholamine synthesizing enzymes. Pharmacol. Rev. 24, 293–309. PubMed

Gottlieb E, and Tomlinson IPM (2005). Mitochondrial tumour suppressors: a genetic and biochemical update. Nat. Rev. Cancer 5, 857–866. 10.1038/nrc1737. PubMed DOI

Gowans GJ, Hawley SA, Ross FA, and Hardie DG (2013). AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab. 18, 556–566. 10.1016/j.cmet.2013.08.019. PubMed DOI PMC

Hachet-Haas M, Converset N, Marchal O, Matthes H, Gioria S, Galzi JL, and Lecat S (2006). FRET and colocalization analyzer–a method to validate measurements of sensitized emission FRET acquired by confocal microscopy and available as an ImageJ Plug-in. Microsc. Res. Tech. 69, 941–956. 10.1002/jemt.20376. PubMed DOI

Hadrava Vanova K, Kraus M, Neuzil J, and Rohlena J (2020). Mitochondrial complex II and reactive oxygen species in disease and therapy. Redox Rep. 25, 26–32. 10.1080/13510002.2020.1752002. PubMed DOI PMC

Hanahan D, and Weinberg RA (2000). The hallmarks of cancer. Cell 100, 57–70. 10.1016/s0092-8674(00)81683-9. PubMed DOI

Hardie DG (2014). AMPK–sensing energy while talking to other signaling pathways. Cell Metab. 20, 939–952. 10.1016/j.cmet.2014.09.013. PubMed DOI PMC

Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG, and Hardie DG (2005). Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2, 9–19. 10.1016/j.cmet.2005.05.009. PubMed DOI

Hemmings HC (1997). Regulatory Protein Modification: Techniques and Protocols (Springer; ).

Hsu PP, and Sabatini DM (2008). Cancer cell metabolism: Warburg and beyond. Cell 134, 703–707. 10.1016/j.cell.2008.08.021. PubMed DOI

Huang Y, Wang LA, Xie Q, Pang J, Wang L, Yi Y, Zhang J, Zhang Y, Chen R, Lan W, et al. (2018). Germline SDHB and SDHD mutations in pheochromocytoma and paraganglioma patients. Endocr. Connect. 7, 1217–1225. 10.1530/EC-18-0325. PubMed DOI PMC

Jana F, Bustos G, Rivas J, Cruz P, Urra F, Basualto-Alarcón C, Sagredo E, Ríos M, Lovy A, Dong Z, et al. (2019). Complex I and II are required for normal mitochondrial Ca(2+) homeostasis. Mitochondrion 49, 73–82. 10.1016/j.mito.2019.07.004. PubMed DOI PMC

Jeanmonod R, Asuka E, and Jeanmonod D (2020). Inborn Errors of Metabolism (StatPearls; ). PubMed

Jochmanova I, and Pacak K (2016). Pheochromocytoma: the first metabolic endocrine cancer. Clin. Cancer Res. 22, 5001–5011. 10.1158/1078-0432.CCR-16-0606. PubMed DOI PMC

Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, and Thompson CB (2005). AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283–293. 10.1016/j.molcel.2005.03.027. PubMed DOI

Jung SH, Hwang HJ, Kang D, Park HA, Lee HC, Jeong D, Lee K, Park HJ, Ko YG, and Lee JS (2019). mTOR kinase leads to PTEN-loss-induced cellular senescence by phosphorylating p53. Oncogene 38, 1639–1650. 10.1038/s41388-018-0521-8. PubMed DOI PMC

Kim JW, and Dang CV (2006). Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res. 66, 8927–8930. 10.1158/0008-5472.CAN-06-1501. PubMed DOI

King KS, Prodanov T, Kantorovich V, Fojo T, Hewitt JK, Zacharin M, Wesley R, Lodish M, Raygada M, Gimenez-Roqueplo AP, et al. (2011). Metastatic pheochromocytoma/paraganglioma related to primary tumor development in childhood or adolescence: significant link to SDHB mutations. J. Clin. Oncol. 29, 4137–4142. 10.1200/JCO.2011.34.6353. PubMed DOI PMC

Kluckova K, Thakker A, Vettore L, Escribano-Gonzalez C, Hindshaw RL, Tearle JLE, Goncalves J, Kaul B, Lavery GG, Favier J, and Tennant DA (2020). Succinate dehydrogenase deficiency in a chromaffin cell model retains metabolic fitness through the maintenance of mitochondrial NADH oxidoreductase function. FASEB J 34, 303–315. 10.1096/fj.201901456R. PubMed DOI

Koh J, Hogue JA, Wang Y, DiSalvo M, Allbritton NL, Shi Y, Olson JA Jr., and Sosa JA (2016). Single-cell functional analysis of parathyroid adenomas reveals distinct classes of calcium sensing behaviour in primary hyperparathyroidism. J. Cell Mol. Med. 20, 351–359. 10.1111/jcmm.12732. PubMed DOI PMC

Korpershoek E, Favier J, Gaal J, Burnichon N, van Gessel B, Oudijk L, Badoual C, Gadessaud N, Venisse A, Bayley JP, et al. (2011). SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J. Clin. Endocrinol. Metab. 96, E1472–E1476. 10.1210/jc.2011-1043. PubMed DOI

Korpershoek E, Pacak K, and Martiniova L (2012). Murine models and cell lines for the investigation of pheochromocytoma: applications for future therapies? Endocr. Pathol. 23, 43–54. 10.1007/s12022-012-9194-y. PubMed DOI PMC

Krebs HA, and Johnson WA (1980). The role of citric acid in intermediate metabolism in animal tissues. FEBS Lett. 117, K1–K10. PubMed

Lee JH, Jang H, Lee SM, Lee JE, Choi J, Kim TW, Cho EJ, and Youn HD (2015). ATP-citrate lyase regulates cellular senescence via an AMPK- and p53-dependent pathway. FEBS J. 282, 361–371. 10.1111/febs.13139. PubMed DOI

Li H, Huang K, Liu X, Liu J, Lu X, Tao K, Wang G, and Wang J (2014). Lithium chloride suppresses colorectal cancer cell survival and proliferation through ROS/GSK-3beta/NF-kappaB signaling pathway. Oxid. Med. Cell. Longev. 2014, 241864. 10.1155/2014/241864. PubMed DOI PMC

Maignan A, Guerin C, Julliard V, Paladino NC, Kim E, Roche P, Castinetti F, Essamet W, Mancini J, Imperiale A, et al. (2017). Implications of SDHB genetic testing in patients with sporadic pheochromocytoma. Langenbeck’s Arch. Surg. 402, 787–798. 10.1007/s00423-017-1564-y. PubMed DOI PMC

Mao D, and Hinds PW (2010). p35 is required for CDK5 activation in cellular senescence. J. Biol. Chem. 285, 14671–14680. 10.1074/jbc.M109.066118. PubMed DOI PMC

Martiniova L, Lai EW, Elkahloun AG, Abu-Asab M, Wickremasinghe A, Solis DC, Perera SM, Huynh TT, Lubensky IA, Tischler AS, et al. (2009). Characterization of an animal model of aggressive metastatic pheochromocytoma linked to a specific gene signature. Clin. Exp. Metastasis 26, 239–250. 10.1007/s10585-009-9236-0. PubMed DOI PMC

Matlac DM, Hadrava Vanova K, Bechmann N, Richter S, Folberth J, Ghayee HK, Ge GB, Abunimer L, Wesley R, Aherrahrou R, et al. (2021). Succinate mediates tumorigenic effects via succinate receptor 1: potential for new targeted treatment strategies in succinate dehydrogenase deficient paragangliomas. Front. Endocrinol. 12, 589451. 10.3389/fendo.2021.589451. PubMed DOI PMC

McClue SJ, and Stuart I (2008). Metabolism of the trisubstituted purine cyclin-dependent kinase inhibitor seliciclib (R-roscovitine) in vitro and in vivo. Drug Metab. Dispos. 36, 561–570. 10.1124/dmd.107.019232. PubMed DOI

McDermott U, Sharma SV, Dowell L, Greninger P, Montagut C, Lamb J, Archibald H, Raudales R, Tam A, Lee D, et al. (2007). Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc. Natl. Acad. Sci. USA 104, 19936–19941. 10.1073/pnas.0707498104. PubMed DOI PMC

Meyer DA, Richer E, Benkovic SA, Hayashi K, Kansy JW, Hale CF, Moy LY, Kim Y, O’Callaghan JP, Tsai LH, et al. (2008). Striatal dysregulation of Cdk5 alters locomotor responses to cocaine, motor learning, and dendritic morphology. Proc. Natl. Acad. Sci. USA 105, 18561–18566. 10.1073/pnas.0806078105. PubMed DOI PMC

Mijit M, Caracciolo V, Melillo A, Amicarelli F, and Giordano A (2020). Role of p53 in the regulation of cellular senescence. Biomolecules 10, E420. 10.3390/biom10030420. PubMed DOI PMC

Morfini G, Szebenyi G, Brown H, Pant HC, Pigino G, DeBoer S, Beffert U, and Brady ST (2004). A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons. EMBO J. 23, 2235–2245. 10.1038/sj.emboj.7600237. PubMed DOI PMC

Nasr P, Gursahani HI, Pang Z, Bondada V, Lee J, Hadley RW, and Geddes JW (2003). Influence of cytosolic and mitochondrial Ca2+, ATP, mitochondrial membrane potential, and calpain activity on the mechanism of neuron death induced by 3-nitropropionic acid. Neurochem. Int. 43, 89–99. 10.1016/s0197-0186(02)00229-2. PubMed DOI

Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, et al. (2004). Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292, 943–951. 10.1001/jama.292.8.943. PubMed DOI

Oakhill JS, Steel R, Chen ZP, Scott JW, Ling N, Tam S, and Kemp BE (2011). AMPK is a direct adenylate charge-regulated protein kinase. Science 332, 1433–1435. 10.1126/science.1200094. PubMed DOI

Pang Z, Bondada V, Sengoku T, Siman R, and Geddes JW (2003). Calpain facilitates the neuron death induced by 3-nitropropionic acid and contributes to the necrotic morphology. J. Neuropathol. Exp. Neurol. 62, 633–643. 10.1093/jnen/62.6.633. PubMed DOI

Pap M, and Cooper GM (1998). Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-Kinase/Akt cell survival pathway. J. Biol. Chem. 273, 19929–19932. 10.1074/jbc.273.32.19929. PubMed DOI

Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, and Tsai LH (1999). Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402, 615–622. 10.1038/45159. PubMed DOI

Pinter K, Grignani RT, Watkins H, and Redwood C (2013). Localisation of AMPK gamma subunits in cardiac and skeletal muscles. J. Muscle Res. Cell Motil. 34, 369–378. 10.1007/s10974-013-9359-4. PubMed DOI PMC

Plattner F, Angelo M, and Giese KP (2006). The roles of cyclin-dependent kinase 5 and glycogen synthase kinase 3 in tau hyperphosphorylation. J. Biol. Chem. 281, 25457–25465. 10.1074/jbc.M603469200. PubMed DOI

Pollard PJ, El-Bahrawy M, Poulsom R, Elia G, Killick P, Kelly G, Hunt T, Jeffery R, Seedhar P, Barwell J, et al. (2006). Expression of HIF-1alpha, HIF-2alpha (EPAS1), and their target genes in paraganglioma and pheochromocytoma with VHL and SDH mutations. J. Clin. Endocrinol. Metab. 91, 4593–4598. 10.1210/jc.2006-0920. PubMed DOI

Pozo K, and Bibb JA (2016). The emerging role of Cdk5 in cancer. Trends Cancer 2, 606–618. 10.1016/j.trecan.2016.09.001. PubMed DOI PMC

Pozo K, Castro-Rivera E, Tan C, Plattner F, Schwach G, Siegl V, Meyer D, Guo A, Gundara J, Mettlach G, et al. (2013). The role of Cdk5 in neuroendocrine thyroid cancer. Cancer Cell 24, 499–511. 10.1016/j.ccr.2013.08.027. PubMed DOI PMC

Rai SK, Bril F, Hatch HM, Xu Y, Shelton L, Kalavalapalli S, Click A, Lee D, Beecher C, Kirby A, et al. (2020). Targeting pheochromocytoma/paraganglioma with polyamine inhibitors. Metabolism 110, 154297. PubMed PMC

Rajgopal Y, and Vemuri MC (2002). Calpain activation and alpha-spectrin cleavage in rat brain by ethanol. Neurosci. Lett. 321, 187–191. 10.1016/s0304-3940(02)00063-0. PubMed DOI

Ranganayaki S, Jamshidi N, Aiyaz M, Rashmi SK, Gayathri N, Harsha PK, Padmanabhan B, and Srinivas Bharath MM (2021). Inhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration. Sci. Rep. 11, 1483. 10.1038/s41598-020-79339-2. PubMed DOI PMC

Ross ME, Evinger MJ, Hyman SE, Carroll JM, Mucke L, Comb M, Reis DJ, Joh TH, and Goodman HM (1990). Identification of a functional glucocorticoid response element in the phenylethanolamine N-methyltransferase promoter using fusion genes introduced into chromaffin cells in primary culture. J. Neurosci. 10, 520–530. PubMed PMC

Rossitti HM, Dutta RK, Larsson C, Ghayee HK, Söderkvist P, and Gimm O. (2020). Activation of RAS signalling is associated with altered cell adhesion in phaeochromocytoma. Int. J. Mol. Sci. 21, E8072. 10.3390/ijms21218072. PubMed DOI PMC

Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, et al. (2012). Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682. 10.1038/nmeth.2019. PubMed DOI PMC

Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, and Cantley LC (2004). The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl. Acad. Sci. USA 101, 3329–3335. 10.1073/pnas.0308061100. PubMed DOI PMC

Solis DC, Burnichon N, Timmers HJLM, Raygada MJ, Kozupa A, Merino MJ, Makey D, Adams KT, Venisse A, Gimenez-Roqueplo AP, and Pacak K (2009). Penetrance and clinical consequences of a gross SDHB deletion in a large family. Clin. Genet. 75, 354–363. 10.1111/j.1399-0004.2009.01157.x. PubMed DOI PMC

Stockholm D, Bartoli M, Sillon G, Bourg N, Davoust J, and Richard I (2005). Imaging calpain protease activity by multiphoton FRET in living mice. J. Mol. Biol. 346, 215–222. 10.1016/j.jmb.2004.11.039. PubMed DOI

Sun KH, de Pablo Y, Vincent F, and Shah K (2008). Deregulated Cdk5 promotes oxidative stress and mitochondrial dysfunction. J. Neurochem. 107, 265–278. 10.1111/j.1471-4159.2008.05616.x. PubMed DOI

Sundstrom L, Greasley PJ, Engberg S, Wallander M, and Ryberg E (2013). Succinate receptor GPR91, a Galpha(i) coupled receptor that increases intracellular calcium concentrations through PLCbeta. FEBS Lett. 587, 2399–2404. 10.1016/j.febslet.2013.05.067. PubMed DOI

Suzuki T, Bridges D, Nakada D, Skiniotis G, Morrison SJ, Lin JD, Saltiel AR, and Inoki K (2013). Inhibition of AMPK catabolic action by GSK3. Mol. Cell 50, 407–419. 10.1016/j.molcel.2013.03.022. PubMed DOI PMC

Tang QL, Xie XB, Wang J, Chen Q, Han AJ, Zou CY, Yin JQ, Liu DW, Liang Y, Zhao ZQ, et al. (2012). Glycogen synthase kinase-3beta, NF-kappaB signaling, and tumorigenesis of human osteosarcoma. J. Natl. Cancer Inst. 104, 749–763. 10.1093/jnci/djs210. PubMed DOI PMC

Tang Z, Li C, Kang B, Gao G, Li C, and Zhang Z (2017). GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 45, W98–W102. 10.1093/nar/gkx247. PubMed DOI PMC

Thoreen CC, and Sabatini DM (2005). AMPK and p53 help cells through lean times. Cell Metab. 1, 287–288. 10.1016/j.cmet.2005.04.009. PubMed DOI

Vander Heiden MG, Cantley LC, and Thompson CB (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033. 10.1126/science.1160809. PubMed DOI PMC

Varghese F, Bukhari AB, Malhotra R, and De A (2014). IHC Profiler: an open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PLoS One 9, e96801. 10.1371/journal.pone.0096801. PubMed DOI PMC

Vial G, Detaille D, and Guigas B (2019). Role of mitochondria in the mechanism(s) of action of metformin. Front. Endocrinol. 10, 294. 10.3389/fendo.2019.00294. PubMed DOI PMC

Wang Q, Liang B, Shirwany NA, and Zou MH (2011). 2-Deoxy-D-glucose treatment of endothelial cells induces autophagy by reactive oxygen species-mediated activation of the AMP-activated protein kinase. PLoS One 6, e17234. 10.1371/journal.pone.0017234. PubMed DOI PMC

Wang Y, Thatcher SE, and Cassis LA (2017). Measuring blood pressure using a noninvasive tail cuff method in mice. Methods Mol. Biol. 1614, 69–73. 10.1007/978-1-4939-7030-8_6. PubMed DOI

Wen Y, Planel E, Herman M, Figueroa HY, Wang L, Liu L, Lau LF, Yu WH, and Duff KE (2008). Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3 beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. J. Neurosci. 28, 2624–2632. 10.1523/JNEUROSCI.5245-07.2008. PubMed DOI PMC

Wu JY, Huang TW, Hsieh YT, Wang YF, Yen CC, Lee GL, Yeh CC, Peng YJ, Kuo YY, Wen HT, et al. (2020). Cancer-derived succinate promotes macrophage polarization and cancer metastasis via succinate receptor. Mol. Cell 77, 213–227.e5. 10.1016/j.molcel.2019.10.023. PubMed DOI

Xie Z, Dong Y, Scholz R, Neumann D, and Zou MH (2008). Phosphorylation of LKB1 at serine 428 by protein kinase C-zeta is required for metforminenhanced activation of the AMP-activated protein kinase in endothelial cells. Circulation 117, 952–962. 10.1161/CIRCULATIONAHA.107.744490. PubMed DOI PMC

Xu Y, Gray A, Hardie DG, Uzun A, Shaw S, Padbury J, Phornphutkul C, and Tseng YT (2017). A novel, de novo mutation in the PRKAG2 gene: infantile-onset phenotype and the signaling pathway involved. Am. J. Physiol. Heart Circ. Physiol. 313, H283–H292. 10.1152/ajpheart.00813.2016. PubMed DOI PMC

Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, and Lowe SW (2007). Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660. 10.1038/nature05529. PubMed DOI PMC

Yang C, Matro JC, Huntoon KM, Ye DY, Huynh TT, Fliedner SMJ, Breza J, Zhuang Z, and Pacak K (2012). Missense mutations in the human SDHB gene increase protein degradation without altering intrinsic enzymatic function. FASEB J 26, 4506–4516. 10.1096/fj.12-210146. PubMed DOI PMC

Zadra G, Batista JL, and Loda M (2015). Dissecting the dual role of AMPK in cancer: from experimental to human studies. Mol. Cancer Res. 13, 1059–1072. 10.1158/1541-7786.MCR-15-0068. PubMed DOI PMC

Zhan Y, Sun X, Li B, Cai H, Xu C, Liang Q, Lu C, Qian R, Chen S, Yin L, et al. (2018). Establishment of a PRKAG2 cardiac syndrome disease model and mechanism study using human induced pluripotent stem cells. J. Mol. Cell. Cardiol. 117, 49–61. 10.1016/j.yjmcc.2018.02.007. PubMed DOI

Zhang S, Lu Z, Mao W, Ahmed AA, Yang H, Zhou J, Jennings N, Rodriguez-Aguayo C, Lopez-Berestein G, Miranda R, et al. (2015). CDK5 regulates paclitaxel sensitivity in ovarian cancer cells by modulating AKT activation, p21Cip1- and p27Kip1-mediated G1 cell cycle arrest and apoptosis. PLoS One 10, e0131833. 10.1371/journal.pone.0131833. PubMed DOI PMC

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, et al. (2001). Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174. 10.1172/JCI13505. PubMed DOI PMC

Disordered-to-ordered transitions in assembly factors allow the complex II catalytic subunit to switch binding partners