Modulation of tissue growth and biomass accumulation by the mitochondrial alternative oxidase

• Grant number: 21/06711-2
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• Start date: February 01, 2022
• End date: January 31, 2027
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Marcos Túlio de Oliveira
• Grantee: Marcos Túlio de Oliveira
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Lucas Anhezini de Araujo ; Marcus Fernandes de Oliveira
• Associated research grant: 14/02253-6 - Investigating the metabolic alterations caused by the transgenic expression of the mitochondrial alternative oxidase of Ciona intestinalis in Drosophila melanogaster, AP.JP
• Associated research grant(s): 22/02370-9 - Multi-user equipment approved in grant 21/06711-2: Imaging System, AP.EMU; 22/02371-5 - Multi-user equipment approved in grant 21/06711-2: real time PCR, AP.EMU
• Associated scholarship(s): 25/05916-0 - Modulation of the Egf signaling pathway by the alternative oxidase, BP.IC; 25/02527-3 - Maintenance and handling of the stock of Drosophila transgenic lines, BP.TT; 25/01481-0 - Effects of the alternative oxidase expression in redox metabolism, BP.PD; + associated scholarships 25/02024-1 - Caracterizing transgenic lines of Drosophila with enginnered mitochondria, BP.TT; 24/20222-2 - The expression of alternative oxidase and its impact on the supramolecular organization of the electron transport system and mitochondrial ultrastructure, BP.DR; 25/00671-0 - Development of a Low Cost Device for Detecting Genetically Modified Drosophila, BP.TT; 24/13345-0 - Determining the nutrient oxidation preferences by mitochondria with the alternative oxidase, BP.IC; 24/05169-8 - Ultrastructural analyzes of mitochondria expressing the alternative oxidase., BP.TT; 24/00482-0 - The contemporary relevance of the model organism Drosophila melanogaster to the biomedical sciences, BP.JC; 24/00483-6 - The contemporary relevance of the model organism Drosophila melanogaster to the biomedical sciences, BP.JC; 23/18123-3 - Fat accumulation in Drosophila expressing the mitochondrial alternative oxidase, BP.TT; 23/10380-7 - Technical support to the experimentation using alternative oxidase-expressing flies, BP.TT; 23/10746-1 - Construction of Drosophila melanogaster lines knockout for Ldh and Gpo1 using the CRISPR technique, BP.IC; 23/05427-4 - Technical support for the studies of modulation of biomass accumulation by the mitochondrial alternative oxidase, BP.TT; 23/04374-4 - Laboratory maintenance and preparation of experimental diets for drosophila expressing alternative oxidase - 2, BP.TT; 22/04256-9 - Modulation of tissue growth and biomass accumulation by the mitochondrial alternative oxidase - Bioinformatics support, BP.TT; 22/05632-4 - Genetic and metabolic interactions among lactate dehydrogenase, glycerol phosphate dehydrogenase and alternative oxidase, BP.PD; 22/02477-8 - Modulation of tissue growth and biomass accumulation by the mitochondrial alternative oxidase - Technical support, BP.TT; 22/03512-1 - Modulation of tissue growth and biomass accumulation by the mitochondrial alternative oxidase - lab maintenance, BP.TT; 22/01509-3 - Alternative oxidase and its genetic, biochemical and physical interactions with the mitochondrial electron transport system of Drosophila melanogaster, BP.MS - associated scholarships

Abstract

Although the mitochondrial alternative oxidase (AOX) is naturally absent in vertebrates and insects, its xenotopic expression in Drosophila and mammalian models has been shown to combat mitochondrial and related dysfunctions, with potential for its deployment as a human therapy enzyme in the future. AOX is a non-proton pumping, mitochondrial inner membrane enzyme that can bypass respiratory chain complexes III and IV, providing an additional pathway for oxygen reduction and coenzyme Q reoxidation and allowing continuing metabolic flux in situations in which the electron transfer system may be compromised. Since being awarded with FAPESP´s Young Investigator grant in 2014, my new lab at UNESP Jaboticabal has been studying how AOX expression influences the development of the fruitfly Drosophila melanogaster, and observed that it accelerates larval metabolism and promotes larval biomass accumulation in a hormetic manner: low-level expression stimulates tissue growth, whereas high levels inhibit it and cause lethality under nutritional limitation. Because mitochondria during tissue growth integrates catabolism of food sources and synthesis of new biomass, we hypothesize that AOX forces electron transfer through the respiratory chain, creating a fine balance between enhanced mitochondrial metabolic flux and excess mitochondrial uncoupling. We thus propose to test this hypothesis in diverse animal models of tissue growth and biomass accumulation, including the developing Drosophila larva, human cancer cells cultured in vitro and insect tumors, using a combination of tissue-specific omics approaches, and analyses of mitochondrial function and supercomplex formation. The ultimate goal is to demonstrate the potential for AOX to control tissue proliferation, establishing the Drosophila larva as a model for understanding cancer metabolism. (AU)

Scientific publications

(7)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

OTHONICAR, MURILO F.; GARCIA, GEOVANA S.; OLIVEIRA, MARCOS T.. The alternative enzymes-bearing tunicates lack multiple widely distributed genes coding for peripheral OXPHOS subunits. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS, v. 1865, n. 3, p. 14-pg., 2024-04-22. (21/06711-2, 17/04372-0, 22/01509-3, 14/02253-6)

OLIVEIRA, MARCOS T.; ANHEZINI, LUCAS; ARAUJO, HELENA M.; OLIVEIRA, MARCUS F.; COUTO-LIMA, CARLOS A.. Boosting life sciences research in Brazil: building a case for a local Drosophila stock center. GENETICS AND MOLECULAR BIOLOGY, v. 47, n. 1, p. 11-pg., 2024-01-01. (17/04372-0, 21/06711-2, 14/02253-6, 22/05632-4)

MARCOS T. OLIVEIRA; LUCAS ANHEZINI; HELENA M. ARAUJO; MARCUS F. OLIVEIRA; CARLOS A. COUTO-LIMA. Boosting life sciences research in Brazil: building a case for a local Drosophila stock center. GENETICS AND MOLECULAR BIOLOGY, v. 47, n. 1, 2024-02-19. (17/04372-0, 21/06711-2, 22/05632-4, 14/02253-6)

RODRIGUES, ANA P. C.; NOVAES, AUDREY C.; CIESIELSKI, GRZEGORZ L.; OLIVEIRA, MARCOS T.. Mitochondrial DNA maintenance in Drosophila melanogaster. BIOSCIENCE REPORTS, v. 42, n. 11, p. 19-pg., 2022-11-01. (21/06711-2, 17/04372-0)

HERVAS, LIVIA SACCANI; DO AMARAL-SILVA, LARA; SARTORI, MARINA RINCON; GUADALUPE-SILVA, ANE; GARGAGLIONI, LUCIANE H.; LERCHNER, JOHANNES; OLIVEIRA, MARCOS TULIO; BICEGO, KENIA CARDOSO. Mitochondrial function in skeletal muscle contributes to reproductive endothermy in tegu lizards (Salvator merianae). ACTA PHYSIOLOGICA, v. 240, n. 7, p. 14-pg., 2024-05-13. (21/10910-0, 21/06711-2, 20/07520-3, 20/10961-1)

COUTO-LIMA, CARLOS ANTONIO; MACHADO, MAIARO CABRAL ROSA; ANHEZINI, LUCAS; OLIVEIRA, MARCOS TULIO; MOLINA, ROBERTO AUGUSTO DA SILVA; DA SILVA, RODRIGO RIBEIRO; LOPES, GABRIEL SARTI; TRINCA, VITOR; COLON, DAVID FERNANDO; PEIXOTO, PABLO M.; et al. EMC1 Is Required for the Sarcoplasmic Reticulum and Mitochondrial Functions in the Drosophila Muscle. BIOMOLECULES, v. 14, n. 10, p. 18-pg., 2024-10-01. (09/54014-7, 18/04017-9, 11/16666-2, 22/05632-4, 12/17890-6, 21/10032-3, 21/06711-2, 18/10089-2, 14/18189-5, 13/21242-2, 15/13396-5, 10/17259-9, 10/11812-8, 16/25325-8)

LERCHNER, JOHANNES; HERVAS, LIVIA S.; BICEGO, KENIA C.; GARCIA, GEOVANA S.; OLIVEIRA, MARCOS T.; HASIC, MERSIHA; KLINGENSPOR, MARTIN; MERTENS, FLORIAN. A device for rapid calorimetric measurements on small biological tissue samples. JOURNAL OF THERMAL ANALYSIS AND CALORIMETRY, v. 149, n. 15, p. 12-pg., 2024-05-18. (21/06711-2, 21/10910-0)