Mitochondrial function and dysfunction: implications for aging and associated diseases

• Grant number: 17/17728-8
• Support Opportunities: Research Projects - Thematic Grants
• Duration: February 01, 2018 - January 31, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Aníbal Eugênio Vercesi
• Grantee: Aníbal Eugênio Vercesi
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Pesquisadores principais: Helena Coutinho Franco de Oliveira ; Roger Frigério Castilho
• Associated researchers: Andrei Carvalho Sposito ; Augusto Shinya Abe ; Marcelo Alves da Silva Mori ; Roberto Docampo
• Associated grant(s): 21/12964-0 - Multi-user equipment approved in grant 2017/17728-8, equipment High Resolution System for measuring the concentration of oxygen in solution, with fluorescence monitoring, AP.EMU; 18/19976-1 - Chip-calorimetric investigations on the energy metabolism of Trypanosoma cruzi, AV.EXT
• Associated scholarship(s): 23/06469-2 - Role of NAD(P)+ transhydrogenase (NNT) in hypothalamic inflammation and brown adipose tissue biogenesis in mice, BP.PD; 20/05202-4 - The role of mitochondrial NAD(P)+ transhydrogenase in monoaminergic neurotransmission and neurodegeneration in mice, BP.PD; 19/20855-7 - The role of mitochondrial NAD(P)-Transhydrogenase in the development of Fatty Liver Disease and aging in mice, BP.PD; + associated scholarships 19/13862-7 - CETP influence on endothelial function and myocardial infarction: possible relation with mitochondrial function, BP.DD; 19/02340-0 - The impact of cholesteryl ester transfer protein (CETP) expression on adiposity in thermoneutral condition and obesogenic diet: focus on white adipose tissue, BP.MS; 17/05487-6 - Mitochondrial function and molecular markers associated with aging in the long-lived red-footed tortoise Chelonoidis carbonaria, BP.PD; 17/02903-9 - Role of CETP expression in the macrophage redox state: possible consequences to inflammation and atherosclerosis, BP.PD; 17/03402-3 - Study of the association of mitochondrial and endoplasmic reticulum membranes in macrophages in the context of hypercholesterolemia: possible relevance for atherosclerosis, BP.PD; 15/17555-0 - Impact of CETP expression on brown and beige adipose tissues and its contribution to the obesity control., BP.PD - associated scholarships

Abstract

In the last 40 years, it has become evident that mitochondria are involved in many cell functions besides energy conversion, such as the control of cell death via calcium and oxygen and nitrogen reactive species signaling. Elevated levels of calcium in the mitochondrial matrix stimulate the generation of reactive oxygen which promote the opening of an unspecific pore in the inner mitochondrial membrane, the Permeability Transition Pore (PTP). Opening of PTP and mitochondrial redox state alterations are associated with cell senescence and death, as well as with the progression of degenerative diseases and with aging. In addition, there is compelling evidence that further studies on the control of PTP opening in aging may open avenues to a better understanding of factors determining longevity. Therefore, the major goal of this project is to advance the knowledge about the mechanisms by which mitochondria exert their regulatory roles in cell life and death and in aging. For this purpose, we plan to use several models (mice, rats, Caenorhabditis elegans, turtles and trypanosomes) to study mitochondrial functions involved in calcium homeostasis, redox (um)balance, longevity, aging and aging-related diseases. The specific objectives are grouped in four research lines: I) nicotinamide nucleotides transhydrogenase, energy metabolism and cell viability; II) mitochondria, dyslipidemias, Atherosclerosis and Obesity; III) mitochondria and aging; and IV) mitochondria and calcium homeostasis in trypanosomatides. Each model will be used to answer specific hypotheses in an integrated and multidisciplinary way with the participation of all principal investigators and collaborators. (AU)

Scientific publications

(37)

(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)

FRANCISCO, ANNELISE; ENGEL, DAIANE F.; FIGUEIRA, TIAGO R.; ROGERIO, FABIO; DE BEM, ANDREZA F.; CASTILHO, ROGER F.. Mitochondrial NAD(P)(+) Transhydrogenase is Unevenly Distributed in Different Brain Regions, and its Loss Causes Depressive-like Behavior and Motor Dysfunction in Mice. Neuroscience, v. 440, p. 210-229, AUG 1 2020. (17/17728-8, 15/22063-0, 18/01360-4, 20/05202-4)

LERCHNER, JOHANNES; SARTORI, MARINA R.; VOLPE, PEDRO O. L.; LANDER, NOELIA; MERTENS, FLORIAN; VERCESI, ANIBAL E.. Direct determination of anaerobe contributions to the energy metabolism of Trypanosoma cruzi by chip calorimetry. ANALYTICAL AND BIOANALYTICAL CHEMISTRY, v. 411, n. 17, p. 3763-3768, JUL 2019. (17/17728-8, 14/08995-4, 17/05487-6, 17/04613-8)

DOCAMPO, ROBERTO; VERCESI, ANIBAL EUGENIO. Mitochondrial Ca2+ and Reactive Oxygen Species in Trypanosomatids. Antioxidants & Redox Signaling, SEP 2021. (17/17728-8)

APARECIDA PEREIRA, ANA PAULA; FIGUEIREDO ANGOLINI, CELIO FERNANDO; DE SOUZA-SPORKENS, JANE CRISTINA; DA SILVA, TOMAZ ANTONIO; FRANCO DE OLIVEIRA, HELENA COUTINHO; PASTORE, GLAUCIA MARIA. Brazilian sunberry (Solanum oocarpum Sendtn): Alkaloid composition and improvement of mitochondrial functionality and insulin secretion of INS-1E cells. Food Research International, v. 148, OCT 2021. (19/08853-9, 17/17728-8, 15/50333-1)

VISACRI, MARILIA B.; QUINTANILHA, JULIA C. F.; DE SOUSA, VANESSA M.; AMARAL, LAIS S.; AMBROSIO, ROSIANE DE F. L.; CALONGA, LUCIANE; CURI, SILVIA F. B. B.; LEME, MAYRA F. DE T.; CHONE, CARLOS T.; ALTEMANI, JOAO M. C.; et al. Can acetylcysteine ameliorate cisplatin-induced toxicities and oxidative stress without decreasing antitumor efficacy? A randomized, double-blind, placebo-controlled trial involving patients with head and neck cancer. CANCER MEDICINE, v. 8, n. 5, p. 2020-2030, MAY 2019. (17/17728-8, 14/04744-7, 14/18294-3, 15/01793-0)

SARTORI, MARINA RINCON; LERCHNER, J.; CASTILHO, R. F.; VOLPE, P. O.; MERTENS, F.; VERCESI, A. E.. hip-calorimetric assessment of heat generation during Ca2+ uptake by digitonin-permeabilized Trypanosoma cruz. JOURNAL OF THERMAL ANALYSIS AND CALORIMETRY, v. 147, n. 7, MAY 2021. (18/19976-1, 17/17728-8, 17/05487-6)

RUAS, JULIANA S.; SIQUEIRA-SANTOS, EDILENE S.; RODRIGUES-SILVA, ERIKA; CASTILHO, ROGER F.. High glycolytic activity of tumor cells leads to underestimation of electron transport system capacity when mitochondrial ATP synthase is inhibited. SCIENTIFIC REPORTS, v. 8, NOV 26 2018. (17/17728-8, 11/50400-0)

CECATTO, CRISTIANE; AMARAL, ALEXANDRE UMPIERREZ; ROGINSKI, ANA CRISTINA; CASTILHO, ROGER FRIGERIO; WAJNER, MOACIR. Impairment of mitochondrial bioenergetics and permeability transition induction caused by major long-chain fatty acids accumulating in VLCAD deficiency in skeletal muscle as potential pathomechanisms of myopathy. TOXICOLOGY IN VITRO, v. 62, FEB 2020. (17/17728-8)

NAVARRO, CLAUDIA D. C.; FRANCISCO, ANNELISE; FIGUEIRA, TIAGO R.; RONCHI, JULIANA A.; OLIVEIRA, HELENA C. F.; VERCESI, ANIBAL E.; CASTILHO, ROGER F.. ichloroacetate reactivates pyruvate-supported peroxide removal by liver mitochondria and prevents NAFLD aggravation in NAD(P)(+) transhydrogenase-null mice consuming a high-fat die. European Journal of Pharmacology, v. 917, FEB 15 2022. (20/05202-4, 19/20855-7, 17/17728-8)

SARTORI, MARINA R.; NAVARRO, CLAUDIA D. C.; CASTILHO, ROGER F.; VERCESI, ANIBAL E.. Aggravation of hepatic lipidosis in red-footed tortoise Chelonoidis carbonaria with age is associated with alterations in liver mitochondria. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR BIOLOGY, v. 260, p. 8-pg., 2022-03-12. (17/05487-6, 17/17728-8, 19/20855-7)

BICEGO, RAFAELA; FRANCISCO, ANNELISE; RUAS, JULIANA S.; SIQUEIRA-SANTOS, EDILENE S.; CASTILHO, ROGER F.. Undesirable effects of chemical inhibitors of NAD(P)(+) transhydrogenase on mitochondrial respiratory function. Archives of Biochemistry and Biophysics, v. 692, p. 12-pg., 2020-10-15. (17/17728-8, 20/05202-4, 15/22063-0)

ASSIS, LEANDRO HENRIQUE DE PAULA; DORIGHELLO, GABRIEL DE GABRIEL; RENTZ, THIAGO; SOUZA, JANE CRISTINA DE; VERCESI, ANIBAL EUGENIO; DE OLIVEIRA, HELENA COUTINHO FRANCO. In Vivo Pravastatin Treatment Reverses Hypercholesterolemia Induced Mitochondria-Associated Membranes Contact Sites, Foam Cell Formation, and Phagocytosis in Macrophages. FRONTIERS IN MOLECULAR BIOSCIENCES, v. 9, p. 17-pg., 2022-03-15. (17/03402-3, 17/17728-8, 17/02903-9, 13/50615-1)

SALERNO, ALESSANDRO G.; RENTZ, THIAGO; DORIGHELLO, GABRIEL G.; MARQUES, ANA CAROLINA; LORZA-GIL, ESTELA; WANSCHEL, AMARYLIS C. B. A.; DE MORAES, AUDREY; VERCESI, ANIBAL E.; OLIVEIRA, HELENA C. F.. Lack of mitochondrial NADP(H)-transhydrogenase expression in macrophages exacerbates atherosclerosis in hypercholesterolemic mice. Biochemical Journal, v. 476, p. 21-pg., 2019-12-01. (11/15103-4, 11/15101-1, 13/05497-0, 11/50400-0, 17/02903-9, 13/07607-8, 17/17728-8)

VERCESI, ANIBAL E.; CASTILHO, ROGER F.; KOWALTOWSKI, ALICIA J.; DE OLIVEIRA, HELENA C. F.; DE SOUZA-PINTO, NADJA C.; FIGUEIRA, TIAGO R.; BUSANELLO, ESTELA N. B.. Mitochondrial calcium transport and the redox nature of the calcium-induced membrane permeability transition. Free Radical Biology and Medicine, v. 129, p. 1-24, DEC 2018. (17/17728-8, 11/50400-0, 06/59786-0, 14/11261-2, 13/07607-8)

RENTZ, THIAGO; WANSCHEL, AMARYLIS C. B. A.; DE CARVALHO MOI, LEONARDO; LORZA-GIL, ESTELA; DE SOUZA, JANE C.; DOS SANTOS, RENATA R.; OLIVEIRA, HELENA C. F.. The Anti-atherogenic Role of Exercise Is Associated With the Attenuation of Bone Marrow-Derived Macrophage Activation and Migration in Hypercholesterolemic Mice. FRONTIERS IN PHYSIOLOGY, v. 11, NOV 23 2020. (17/17728-8, 13/07607-8)

LORZA-GIL, ESTELA; GARCIA-AREVALO, MARTA; FAVERO, BIANCA CRISTINE; GOMES-MARCONDES, MARIA CRISTINA C.; OLIVEIRA, HELENA C. F.. Diabetogenic effect of pravastatin is associated with insulin resistance and myotoxicity in hypercholesterolemic mice. JOURNAL OF TRANSLATIONAL MEDICINE, v. 17, n. 1, AUG 27 2019. (17/17728-8)

FIGUEIRA, TIAGO R.; FRANCISCO, ANNELISE; RONCHI, JULIANA A.; DOS SANTOS, GUILHERME R. R. M.; DOS SANTOS, WILLIAM; TREBERG, JASON R.; CASTILHO, ROGER F.. NADPH supply and the contribution of NAD(P)(+) transhydrogenase (NNT) to H2O2 balance in skeletal muscle mitochondria. Archives of Biochemistry and Biophysics, v. 707, AUG 15 2021. (11/51800-1, 20/05202-4, 18/04559-6, 17/17728-8)

DORIGHELLO, GABRIEL G.; ROVANI, JULIANA C.; PAIM, BRUNO A.; RENTZ, THIAGO; ASSIS, LEANDRO H. P.; VERCESI, ANIBAL E.; OLIVEIRA, HELENA C. F.. Mild Mitochondrial Uncoupling Decreases Experimental Atherosclerosis, A Proof of Concept. JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS, v. 29, n. 6, p. 14-pg., 2022-01-01. (17/17728-8, 13/07607-8, 17/02903-9, 14/02819-0, 17/03402-3)

ROGINSKI, ANA CRISTINA; WAJNER, ALESSANDRO; CECATTO, CRISTIANE; WAJNER, SIMONE MAGAGNIN; CASTILHO, ROGER FRIGERIO; WAJNER, MOACIR; AMARAL, ALEXANDRE UMPIERREZ. Disturbance of bioenergetics and calcium homeostasis provoked by metabolites accumulating in propionic acidemia in heart mitochondria of developing rats. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v. 1866, n. 5, MAY 1 2020. (17/17728-8)

DORIGHELLO, GABRIEL G.; ASSIS, LEANDRO H. P.; RENTZ, THIAGO; MORARI, JOSEANE; SANTANA, MONIQUE F. M.; PASSARELLI, MARISA; RIDGWAY, NEALE D.; VERCESI, ANIBAL E.; OLIVEIRA, HELENA C. F.. Novel Role of CETP in Macrophages: Reduction of Mitochondrial Oxidants Production and Modulation of Cell Immune-Metabolic Profile. ANTIOXIDANTS, v. 11, n. 9, p. 17-pg., 2022-09-01. (13/07607-8, 17/17728-8, 17/02903-9, 19/18431-4, 21/02401-9, 17/03402-3)

ASSIS, LEANDRO HENRIQUE DE PAULA; DORIGHELLO, GABRIEL DE GABRIEL; DE OLIVEIRA, HELENA COUTINHO FRANCO. Pro-inflammatory polarization of macrophages is associated with reduced endoplasmic reticulum-mitochondria interaction. Biochemical and Biophysical Research Communications, v. 606, p. 7-pg., 2022-05-28. (13/50615-1, 17/17728-8, 17/02903-9, 17/03402-3)

OLIVEIRA, HELENA C. F.; VERCESI, ANIBAL E.. Mitochondrial bioenergetics and redox dysfunctions in hypercholesterolemia and atherosclerosis. MOLECULAR ASPECTS OF MEDICINE, v. 71, FEB 2020. (17/17728-8)

MARQUES, ANA C.; BUSANELLO, ESTELA N. B.; DE OLIVEIRA, DIOGO N.; CATHARINO, RODRIGO R.; OLIVEIRA, HELENA C. F.; VERCESI, ANIBAL E.. Coenzyme Q10 or Creatine Counteract Pravastatin-Induced Liver Redox Changes in Hypercholesterolemic Mice. FRONTIERS IN PHARMACOLOGY, v. 9, JUN 27 2018. (11/50400-0, 17/17728-8, 13/07607-8)

LERCHNER, J.; SARTORI, M. R.; VOLPE, P. O.; FORSTER, S.; MAZIK, M.; VERCESI, A. E.; MERTENS, F.. Segment fusion chip calorimetry: a new method for the investigation of fast reactions. JOURNAL OF THERMAL ANALYSIS AND CALORIMETRY, FEB 2021. (18/19976-1, 17/17728-8, 17/05487-6)

FRANCISCO, ANNELISE; RONCHI, JULIANA A.; NAVARRO, CLAUDIA D. C.; FIGUEIRA, TIAGO R.; CASTILHO, ROGER F.. Nicotinamide nucleotide transhydrogenase is required for brain mitochondrial redox balance under hampered energy substrate metabolism and high-fat diet. Journal of Neurochemistry, v. 147, n. 5, p. 663-677, DEC 2018. (17/17728-8, 15/22063-0)

FRANCISCO, ANNELISE; FIGUEIRA, TIAGO REZENDE; CASTILHO, ROGER FRIGERIO. Mitochondrial NAD(P)(+) Transhydrogenase: From Molecular Features to Physiology and Disease. Antioxidants & Redox Signaling, AUG 2021. (17/17728-8, 20/05202-4)

BATALHA, CAIO M. P. F.; VERCESI, ANIBAL EUGENIO; SOUZA-PINTO, NADJA C.. The Many Roles Mitochondria Play in Mammalian Aging. Antioxidants & Redox Signaling, JAN 2022. (17/04372-0, 17/17728-8)

LERCHNER, J.; SARTORI, M. R.; VOLPE, P. O.; FORSTER, S.; MAZIK, M.; VERCESI, A. E.; MERTENS, F.. Segment fusion chip calorimetry: a new method for the investigation of fast reactions. JOURNAL OF THERMAL ANALYSIS AND CALORIMETRY, v. 147, n. 3, p. 2253-2263, FEB 2022. (17/17728-8, 17/05487-6, 18/19976-1)

ARTICO, LEONARDO LUIS; RUAS, JULIANA SILVEIRA; TEIXEIRA JUNIOR, JOSE RICARDO; MIGITA, NATACHA AZUSSA; SEGUCHI, GUSTAVO; SHI, XINGHUA; BRANDALISE, SILVIA REGINA; CASTILHO, ROGER FRIGERIO; YUNES, JOSE ANDRES. IGFBP7 Fuels the Glycolytic Metabolism in B-Cell Precursor Acute Lymphoblastic Leukemia by Sustaining Activation of the IGF1R-Akt-GLUT1 Axis. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 11, p. 14-pg., 2023-06-02. (19/04943-3, 22/04464-0, 17/17728-8, 14/20015-5, 12/12802-1)

SARTORI, MARINA R.; NAVARRO, CLAUDIA D. C.; CASTILHO, ROGER F.; VERCESI, ANIBAL E.. nhanced resistance to Ca2+-induced mitochondrial permeability transition in the long-lived red-footed tortoise Chelonoidis carbonari. Journal of Experimental Biology, v. 225, n. 1, JAN 2022. (17/17728-8, 19/20855-7, 17/05487-6)

ALBERICI, LUCIANE C.; OLIVEIRA, HELENA C. F.. Mitochondrial Adaptive Responses to Hypertriglyceridemia and Bioactive Lipids. Antioxidants & Redox Signaling, v. 36, n. 13, p. 16-pg., 2021-12-31. (13/07607-8, 17/17728-8, 18/10089-2)

OLIVEIRA, HELENA C. F.; RAPOSO, HELENA F.; JIANG, XC. Cholesteryl Ester Transfer Protein and Lipid Metabolism and Cardiovascular Diseases. LIPID TRANSFER IN LIPOPROTEIN METABOLISM AND CARDIOVASCULAR DISEASE, v. 1276, p. 11-pg., 2020-01-01. (13/07607-8, 17/17728-8, 15/17555-0)

SARTORI, MARINA RINCON; LERCHNER, J.; CASTILHO, R. F.; VOLPE, P. O.; MERTENS, F.; VERCESI, A. E.. Chip-calorimetric assessment of heat generation during Ca2+ uptake by digitonin-permeabilized Trypanosoma cruzi. JOURNAL OF THERMAL ANALYSIS AND CALORIMETRY, v. 147, n. 7, p. 9-pg., 2021-05-23. (17/05487-6, 18/19976-1, 17/17728-8)

CECATTO, CRISTIANE; AMARAL, ALEXANDRE UMPIERREZ; WAJNER, ALESSANDRO; WAJNER, SIMONE MAGAGNIN; CASTILHO, ROGER FRIGERIO; WAJNER, MOACIR. Disturbance of mitochondrial functions associated with permeability transition pore opening induced by cis-5-tetradecenoic and myristic acids in liver of adolescent rats. MITOCHONDRION, v. 50, p. 1-13, JAN 2020. (17/17728-8)

DE-BRITO, NATALIA M.; DUNCAN-MORETTI, JULIA; DA-COSTA, HAYANDRA C.; SALDANHA-GAMA, ROBERTA; PAULA-NETO, HEITOR A.; DORIGHELLO, GABRIEL G.; SIMOES, RAFAEL L.; BARJA-FIDALGO, CHRISTINA. Aerobic glycolysis is a metabolic requirement to maintain the M2-like polarization of tumor-associated macrophages. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v. 1867, n. 2, FEB 2020. (17/17728-8)

SALERNO, ALESSANDRO G.; RENTZ, THIAGO; DORIGHELLO, GABRIEL G.; MARQUES, ANA CAROLINA; LORZA-GIL, ESTELA; WANSCHEL, AMARYLIS C. B. A.; DE MORAES, AUDREY; VERCESI, ANIBAL E.; OLIVEIRA, HELENA C. F.. Lack of mitochondrial NADP(H)-transhydrogenase expression in macrophages exacerbates atherosclerosis in hypercholesterolemic mice. Biochemical Journal, v. 476, n. 24, p. 3769-3789, DEC 2019. (11/15101-1, 11/15103-4, 11/50400-0, 13/05497-0, 17/17728-8, 13/07607-8, 17/02903-9)

SILVA, ELLEN A. A.; DALLA COSTA, ANA P. P.; RUAS, JULIANA S. S.; SIQUEIRA-SANTOS, EDILENE S. S.; FRANCISCO, ANNELISE; CASTILHO, ROGER F. F.. Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation. CELLS, v. 12, n. 5, p. 17-pg., 2023-03-01. (17/17728-8, 20/05202-4)