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

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 (UPRmt) to guarantee the mitochondrial integrity and function. However, the role of mitonuclear imbalance and UPRmt 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 UPRmt 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 UPRmt in hypothalamic cells.

Increasing energy expenditure through exercise and low ambient temperature offers oxidative protection to the hypothalamus after high‐fat feeding to mice

“…Indeed, both experimental interventions were able to restore mtDNA content in the hypothalamus of DIO mice to the level observed in healthy lean controls. Similarly, in a recent study aiming to evaluate the role of hypothalamic mtDNA and mitochondrial proteostasis in the control of the energy homeostasis in mice, BW loss in response to physical training was associated with induction of the expression of mtDNA‐related genes in the hypothalamus 47 . Accordingly, the study showed that hypothalamic transcripts from nuclear DNA were suppressed after exercise.…”

“…Similarly, in a recent study aiming to evaluate the role of hypothalamic mtDNA and mitochondrial proteostasis in the control of the energy homeostasis in mice, BW loss in response to physical training was associated with induction of the expression of mtDNA-related genes in the hypothalamus. 47 Accordingly, the study showed that hypothalamic transcripts from nuclear DNA were suppressed after exercise. Moreover, our study shows that increasing EE through exercise reduces the level of nucleic acid oxidative damage that results The action of ET and a lower ambient temperature with respect to combating the causes and neutralizing the effects of oxidative stress in hypothalamic cells is of notable importance because oxidative damage plays a prominent role in the development of neurodegenerative diseases.…”

Therapeutic Potential of Nutritional Food for Healthy Cardiovascular System-Molecular Mechanism

“…Mitochondria have their deoxyribonucleic acid (DNA) and genetic program that is separate from the DNA found in the nucleus of the cell. Exercise is the best stimulus for making new mitochondria [54]. When blood glucose and oxygen levels, as well as mitochondrial capacity, are both optimal, everything works well [55,56].…”

Mitochondrially-Targeted Therapeutic Strategies for Alzheimer’s Disease

“…Simultaneously, EE improves mtDNA repair capacity in the mouse hippocampus and activates mitochondrial uncoupling proteins (UCP) that regulate mitochondrial proliferation [ 296 ] and production of mitochondrial-derived ROS [ 297 , 298 ]. At the same time EE alters mitochondrial proteostasis and mitochondrial unfolded protein response (UPRmt) markers and stimulates the OXPHOS component from mtDNA in (neuropeptide Y) NPY-producing neurons in the lateral hypothalamus of mice [ 299 ]. Since EE has been shown to be helpful in retarding the progress of Parkinson’s disease (PD) [ 300 ], it may be a promising therapeutic option for AD [ 301 ].…”