Healthy skeletal muscle is critical to our overall quality of life. In turn, muscle health depends on the ability of mitochondria to perform their many essential functions. David Hood and his colleagues at York University in Toronto recently described the complex relationship between muscle use and mitochondrial health. Their review was published in a recent issue of the Journal of Sport and Health Science.

Many aspects of the quality of life involve mitochondrial health. For example, exercise promotes mitochondrial biogenesis, networking and efficiency. However, lack of exercise results in decreased mitochondrial quality. In addition, it can increase the activity of the innate immune system. Mitochondrial damage-associated molecular patterns (DAMPs) resulting from the activation of the immune system can also affect muscle function.

In this review, the authors describe the effects on mitochondrial biogenesis, fusion, fission and mitophagy. More specifically, they review the involvement of nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome complex activation with mitochondrial quality. That complex regulates innate immunity and cell death by controlling caspase-1, interleukin-1b and -18, and gasdermin-D. Despite considerable work in these areas, the relationship between metabolic states and these compounds is still unclear.

The review provides an overview of the state of current research into how muscle activity, mitochondrial health, and the immune system are linked in a complex system. Interestingly, modulating skeletal muscle activity may suggest a promising therapeutic strategy to manage inflammatory responses in skeletal muscle. Further research is needed to determine the value of this possible treatment strategy.

A Conversation with Dr. Hood.

MitoWorld: This review again highlights the multiple and unexpected activities of mitochondria. Can you give us some idea of where you future is heading?

Hood: The future in this field is moving toward understanding the role of mitochondria as a signaling hub for the activation of retrograde pathways back to the nucleus.  These signals activate the transcription of genes that ultimately alter the cellular phenotype.  This varies considerably among tissues with divergent mitochondrial morphologies and metabolic functions (e.g., liver vs. muscle vs. heart) and also between health and disease states.  This makes studying mitochondria very interesting.

MitoWorld: You note that other signaling molecules (other than the NLRP3 complex) might be involved. Can you speculate on what those might be? Do you plan to follow up on them?

Hood: Mitochondria are the only organelles with their own separate genome, which adds to their fascination.  Mitochondrial defects can lead to the release of mtDNA into the cytoplasm of the cell, leading to the activation of a separate immune response.  Some of this mtDNA actually also leaves the cell and can be measured in blood, providing a useful biomarker for cellular stress.

MitoWorld: You ask an interesting question in the limitations section about possible different responses to exercise programs other than endurance exercise. Any thought?

The immune response to exercise varies considerably with exercise intensity.  Thus, it would be interesting to evaluate the innate immune response within muscle as a function of high-intensity interval training (HIIT) or with a strenuous bout of resistance exercise.

MitoWorld: Some mitochondrial diseases feature extreme fatigue in patients. Could even modest exercise help them or is that an entirely different question?

Hood: Patients with mitochondrial disease obviously have defective mitochondria and energy production, leading to rapid fatigue during exertion.  These defective mitochondria likely elicit a heightened immune response.  Regular exercise is known to improve muscle function, work capacity, oxygen consumption and performance in mtDNA disease patients, but it is not yet known whether exercise can attenuate the immune signaling in these patients.

MitoWorld: As you note, it is easy to imagine exercise as a therapeutic strategy to improve mitochondrial health and to moderate the innate immune system? Can you expand on how this might be done?

Hood: We have shown that the exaggerated immune signaling pathway evident in aged muscle is strongly attenuated with regular exercise (Khemraj, P et al. J. Appl. Physiol. 2025).  This involves an exercise-induced reduction in the expression of NLRP3 and downstream signaling, and it shows that exercise is a very promising therapeutic for maintaining and preserving muscle health as we age.

MitoWorld: We are always interested in learning what it was that brought you to study mitochondria. Can you describe that?

Hood: My PhD thesis many years ago involved the study of an amino acid metabolizing enzyme that is located in muscle mitochondria.  That research helped me develop an interest in mitochondria.  And since I was always fairly athletic, I began to wonder what exercise also did to mitochondria.  I never looked back.

Reference

Khemraj P, Kuznyetsova A, Hood DA (2025) Adaptations in mitochondrial quality control and interactions with innate immune signaling within skeletal muscle: A narrative review. Journal of Sport and Health Science 15: 101049.

https://www.sciencedirect.com/science/article/pii/S2095254625000274