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

• Grant number: 21/06711-2
• Support type: Research Grants - Young Investigators Grants - Phase 2
• Duration: February 01, 2022 - January 31, 2027
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal researcher: Marcos Túlio de Oliveira
• Grantee: Marcos Túlio de Oliveira
• Home Institution: Faculdade de Ciências Agrárias e Veterinárias (FCAV). Universidade Estadual Paulista (UNESP). Campus de Jaboticabal. Jaboticabal , SP, Brazil
• Assoc. 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 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): 22/05632-4 - Genetic and metabolic interactions among lactate dehydrogenase, glycerol phosphate dehydrogenase and alternative oxidase, BP.PD; 22/04256-9 - Modulation of tissue growth and biomass accumulation by the mitochondrial alternative oxidase - Bioinformatics support, BP.TT; 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

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)