Mitochondrial genome instability disrupts brown adipose tissue through pseudohypoxia-iron-NAD⁺ axis

Brown adipose tissue (BAT) is a mitochondria-rich organ responsible for generating heat through high oxidative capacity. However, the impact of mitochondrial dysfunction on BAT function and metabolism is not fully understood. Researchers have utilized the Deletor mouse model to investigate the effects of progressive mtDNA deletion disease on BAT identity and metabolism.

In Deletor mice, BAT undergoes significant remodeling, characterized by structural damage, loss of thermogenic function, pseudohypoxic signaling, iron dysregulation, and NAD+/NADH redox imbalance. These changes result in a failure to produce heat when exposed to cold and an inability to switch to fatty acid oxidation. Metabolomic analysis revealed altered TCA cycle intermediates, a shift in glycolysis, and accumulation of specific amino acids.

Further investigation showed that inhibiting PHD, a protein involved in pseudohypoxia signaling, worsened the disease-associated features. Additionally, suppressing HIF-1, another factor in the pseudohypoxic pathway, attenuated the stress response. Nicotinamide riboside, a compound that boosts NAD+, alleviated the disease's metabolic and transcriptional abnormalities, restoring the NAD+/NADH balance, suppressing the ISRmt, iron-stress, and pseudohypoxic gene programs, and correcting irregularities in carnitine and acylcarnitine levels.

These findings suggest that the pseudohypoxia-iron-NAD+ axis plays a crucial role in BAT dysfunction in mitochondrial disease. By targeting this axis, it may be possible to develop therapeutic strategies to restore BAT function and improve the metabolic health of those affected by mitochondrial disorders.