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Exercise alters the mitochondrial proteostasis and induces the mitonuclear imbalance and UPRmt in the hypothalamus of mice

2021; Nature Portfolio; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41598-021-82352-8

2045-2322

Renata Rosseto Braga, Bárbara Crisol, Rafael S. Brícola, Marcella Ramos Sant’Ana, Susana Castelo Branco Ramos Nakandakari, Suleyma O. Costa, Patrícia O. Prada, Adelino Sánchez Ramos da Silva, Leandro Pereira de Moura, José Rodrigo Pauli, Dennys E. Cintra, Eduardo R. Ropelle,

Exercise and Physiological Responses

Abstract The maintenance of mitochondrial activity in hypothalamic neurons is determinant to the control of energy homeostasis in mammals. Disturbs in the mitochondrial proteostasis can trigger the mitonuclear imbalance and mitochondrial unfolded protein response (UPR mt ) to guarantee the mitochondrial integrity and function. However, the role of mitonuclear imbalance and UPR mt in hypothalamic cells are unclear. Combining the transcriptomic analyses from BXD mice database and in vivo experiments, we demonstrated that physical training alters the mitochondrial proteostasis in the hypothalamus of C57BL/6J mice. This physical training elicited the mitonuclear protein imbalance, increasing the mtCO-1/Atp5a ratio, which was accompanied by high levels of UPR mt markers in the hypothalamus. Also, physical training increased the maximum mitochondrial respiratory capacity in the brain. Interestingly, the transcriptomic analysis across several strains of the isogenic BXD mice revealed that hypothalamic mitochondrial DNA-encoded genes were negatively correlated with body weight and several genes related to the orexigenic response. As expected, physical training reduced body weight and food intake. Interestingly, we found an abundance of mt-CO1, a mitochondrial DNA-encoded protein, in NPY-producing neurons in the lateral hypothalamus nucleus of exercised mice. Collectively, our data demonstrated that physical training altered the mitochondrial proteostasis and induced the mitonuclear protein imbalance and UPR mt in hypothalamic cells.