Sex differences in the regulation of hepatic mitochondrial turnover following physical activity: do males need more quality control than females?

The global rise of hepatic steatosis and non-alcoholic fatty liver disease (NAFLD) has spurred considerable interest in understanding how liver fat metabolism is regulated at fundamental levels. Endogenous control by mitochondrial respiratory activity has been viewed as a critical determinant given the high demand for β-oxidation to support gluconeogenesis, ketogenesis and the energetic demand of the liver itself (Kerner & Hoppel, 2000). Evidence that mitochondrial dysfunction can precede the development of insulin resistance and hepatic steatosis (Rector et al. 2010) positioned mitochondrial bioenergetics as a potential therapeutic target to treat this condition. Indeed, a potent enhancer of hepatic mitochondrial function is exercise, whereby only a few weeks of voluntary wheel running in rodents increased markers of oxidative capacity (Fletcher et al. 2014) and protected against hepatic steatosis (Rector & Thyfault, 2011). However, the mechanisms by which liver mitochondria adaptations to exercise are regulated remains unknown, and the degree to which sex determines mitochondrial respiratory capacities and improvements with exercise are uncharacterized. Given that the risk for developing NAFLD may differ between sexes, investigating the sex-specific relationship between mitochondrial function and exercise adaptations could lead to new understandings of how sedentarism increases lipid stress on the liver. To address these uncertainties, in a study published in the current issue of The Journal of Physiology, Von Schulze et al. (2018) compared hepatic mitochondrial responses to 4 weeks of voluntary wheel running in male and female mice. Rather than focusing on hepatic steatosis per se, they recognized the importance of first establishing the fundamental mechanisms regulating hepatic mitochondrial turnover in the absence of disease. They considered the prevailing model that posits that mitochondrial turnover is a balance between biogenesis and degradation through mitophagy – a process of removing mitochondria of poor quality. With regard to biogenesis, they hypothesized that the well-characterized transcriptional co-activator PGC-1α would mediate biogenic stimulation whereas the mitophagic regulator BNIP3 would be essential for degradation. The synergistic action of both biogenic and mitophagic pathways would result in an improved mitochondrial respiratory capacity following exercise. They also hypothesized that females would demonstrate larger increases in respiratory capacity, given their greater reliance on fat oxidation and apparent protection from steatosis, at least in rats (Hart-Unger et al. 2017). In non-exercised animals, females generally had greater mitochondrial respiratory capacities than males when tested with multiple substrates, while males generally had greater capacities for H2O2 emission – a reactive oxygen species that can modulate cellular function through redox signalling and potentially oxidative stress. A remarkable finding was that sedentary males have greater mitophagy, suggesting they require higher rates of degradation to maintain mitochondrial quality. However, it is difficult to discern if the lower respiratory capacities and greater H2O2 emission in males are a result of this greater mitophagic flux or indeed represent the need for greater mitophagy. Following 4 weeks of voluntary wheel running, males and females generally maintained their respiratory capacities, which contrasted with the hypothesis that exercise would increase mitochondrial capacity, although male mitochondria appeared more coupled, suggesting that ATP production became more efficient, like females. However, exercise decreased mitophagy in males down to levels that matched the low rates seen in females. This finding is remarkable in that it suggests males require exercise to maintain mitochondrial quality, removing the need for high rates of mitophagy. Females, on the other hand, do not have high rates of mitophagy during sedentarism and thus are able to maintain high respiratory capacities, even without exercise or high rates of mitochondrial turnover. An alternative perspective is that the voluntary wheel running group represents the control, given that mice habitually engage in physical activity when presented with a wheel, and sedentarism represents the intervention (Booth & Lees, 2006). Viewed in this light, females seem to be resistant to sedentarism in that they maintained high mitochondrial respiratory capacities, lower H2O2 emission potential, and low rates of mitophagy. Males, on the other hand, experienced greater mitophagy in response to sedentarism, suggesting they are more dependent on exercise to maintain mitochondrial quality. With this in mind, it is interesting that males demonstrate lower respiratory capacities and higher H2O2 emission potentials than females, regardless of the level of physical (in)activity. This information should guide investigations to examine how females are more protected against hepatic steatosis and NAFLD during sedentarism vs. males. An interesting corollary is the finding that the risk for NAFLD increases during menopause in women (Clark, 2006). The present findings might suggest that the sex-differences in hepatic mitochondrial bioenergetic capacities and mitophagy seen in young rodents may disappear as females enter menopause, whereby female mitochondrial characteristics may become less efficient and approach the relative inferior qualities and capacities seen in males. These mitochondrial response characterizations were extensive, and yet they were repeated in mice with liver-specific deficiencies in PGC-1α and BNIP3 – models that were used to attenuate mitochondrial biogenesis and mitophagy, respectively. In general, these models demonstrated similar responses to exercise to controls. This finding suggests the changes in mitophagy seen in males after exercise do not require BNIP3 and instead rely on alternative mitophagy pathways (e.g. Parkin). The investigation by Von Schulze et al. (2018) highlights the critical importance of comparing sex differences in studies. To this end, the study suggests that physical activity is essential for males to maintain mitochondrial integrity in conjunction with more coupled respiration like females, even though their bioenergetic capacities may remain lower than females. These findings lay a foundation for determining whether such dimorphism is a novel mechanism determining sex differences in the risk for developing steatosis and NAFLD. None declared. Both authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None.

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