The following two examples — one on age-related cataracts, and one on Steatotic Liver Disease (SLD) — both illustrate how cells try to compensate for oxidative stress, and what happens when those compensatory systems eventually fail.
Oxidative Stress and Cataract Formation
Huang et al. (2022) investigated how biliverdin reductase A protects lens epithelial cells from the oxidative stress implicated in age-related cataracts, by recycling biliverdin back to the antioxidant bilirubin. They collected lens samples (cortex and epithelial cell) from patients (mostly ages 55–65) undergoing lens replacement surgery — either for cataracts or, as controls, for presbyopia. Patients with nuclear cataracts had lower levels of both biliverdin reductase A and bilirubin compared to controls; this pattern was not seen in cortical or posterior subcapsular cataracts.
To dig into the mechanism, the researchers turned to mouse lens epithelial cells aged for either 4 or 15 weeks, and then exposed to hydrogen peroxide for a week. Younger cells mounted a robust response — ramping up both biliverdin reductase A and bilirubin production, and moving biliverdin reductase A into the nucleus. Older cells couldn’t do either: bilirubin wasn’t efficiently restored, and biliverdin reductase A stayed in the cytoplasm rather than entering the nucleus (older cells had lower nuclear biliverdin reductase A even before hydrogen peroxide treatment).
Knocking down biliverdin reductase A made the consequences of hydrogen peroxide exposure worse across the board: greater mitochondrial membrane potential depolarization, more reactive oxygen species in the mitochondria, increased apoptosis, and fewer surviving lens epithelial cells. Supplementing bilirubin before hydrogen peroxide exposure prevented these effects, leading the researchers to conclude that biliverdin reductase A’s job of restoring bilirubin from its oxidized form (biliverdin) is essential for preventing both mitochondrial dysfunction and premature cellular aging in the lens.
Epithelial cells in cell cycle arrest had lower biliverdin reductase A and bilirubin, while boosting biliverdin reductase A expression could push cells back through the cell cycle. That connects to other research the authors cite showing that excessive reactive oxygen species pushing lens epithelial cells into cell cycle arrest can contribute to the loss of lens transparency seen in cataracts.
One interesting detail: because bilirubin is lipophilic, it mainly neutralizes reactive oxygen species that would damage the cell membrane, while the water-soluble antioxidant glutathione — also found depleted in the nucleus of aging lenses with nuclear cataracts— protects the cell’s hydrophilic proteins instead. Maintaining lens transparency appears to require healthy levels of both lipophilic and hydrophilic antioxidants. The authors describe other studies where biliverdin reductase A was seen to activate Nrf2, a transcription factor that triggers production of a broad range of additional antioxidant enzymes — suggesting its protective role extends beyond bilirubin recycling alone.
Compromised Mitochondrial Respiration in Steatotic Liver Disease
A different kind of oxidative-stress scenario shows up in the progression from MASLD (Metabolic dysfunction-associated steatotic liver disease) to MASH (Metabolic dysfunction-associated steatohepatitis): mitochondrial respiration is actually higher than normal in MASLD, but drops below normal once the disease progresses to MASH. Koliaki et al. (2015) suggest that the elevated respiration seen in MASLD reflects the liver adapting to compensate for insulin resistance. But as the disease progresses, mitochondria become increasingly “leaky,” and the compensation can no longer keep up. Notably, higher respiration doesn’t necessarily mean more ATP — when the respiratory chain becomes uncoupled from ATP production, the cell can be working harder while producing less usable energy. The authors also cite research showing misshapen mitochondria in MASH, suggesting that the higher mitochondrial numbers seen in the disease may reflect a failure to properly clear out damaged mitochondria rather than healthy proliferation.
There’s a self-reinforcing problem here: the compensatory ramping-up of the respiratory chain likely generates more reactive oxygen species as a side effect, which impairs mitochondrial function further as the disease advances — a feedback loop where the very adaptation meant to help ends up accelerating the underlying damage.
The Takeaway
Both the lens and the liver show cells attempting to compensate for oxidative stress — through antioxidant systems like biliverdin reductase A and bilirubin, or through ramped-up mitochondrial respiration — and both show what happens when that compensation eventually breaks down: increased reactive oxygen species, mitochondrial dysfunction, and tissue damage that drives disease progression.
References
Huang, Y., Liu, Y., Yu, S., Li, W., Li, J., Zhao, B., Hu, X., & Jin, H. (2022). Biliverdin reductase A protects lens epithelial cells against oxidative damage and cellular senescence in age-related cataract. Oxidative Medicine & Cellular Longevity, 1–18.
Koliaki, C., Szendroedi J., Kaul K., Jelenik T., Nowotny P., Jankowiak F., Herder C., Carstensen M., Krausch M., Knoefel W.T., Schlensak M., & Roden M. (2015). Adaptation of Hepatic Mitochondrial Function in Humans with Non-Alcoholic Fatty Liver Is Lost in Steatohepatitis. Cell Metabolism, 21.
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