Mitochondria and peroxisomes communicate to maintain lipid homeostasis, but how the latter adjust to mitochondrial dysfunction remains unclear. Here, we show that loss of complex I subunit NDUFS4 in mouse fibroblasts leads to impaired mitochondrial fatty acid oxidation, resulting in the accumulation of triacylglycerol and lipid droplet (LD) expansion. In this context, peroxisomal biogenesis is upregulated, but their β-oxidation capacity is impaired, suggesting an adaptive yet ineffective response. Additionally, lipid overload using a very-long-chain fatty acid (VLCFA) leads to peroxisomal proliferation but prevents LD expansion when peroxisomal β-oxidation is compromised. The data demonstrated that proper peroxisomal processing is necessary for lipid storage under mitochondrial stress conditions. Our findings reveal a peroxisomal maladaptive remodelling response that fails to compensate for mitochondrial dysfunction, leading to disruptions in LD homeostasis. We propose a critical axis involving peroxisomes-LD-mitochondria that buffers metabolic stress in mitochondrial diseases. Schematic representation of disrupted fatty acid metabolism in NDUSF4-KO cells, highlighting impaired mitochondrial fatty acid activation by ACSL1 and import via CPTI/II, leading to decreased mitochondrial β-oxidation and TCA cycle flux. Consequently, free fatty acids are stored in lipid droplets (LDs). Peroxisomes (PO) present a maladaptive response where, in response to impaired mitochondrial β-oxidation, they increase in numbers but fail to compensate metabolically. In fact, peroxisomal β-oxidation is also compromised, showing a decrease in markers for this pathway (e.g., ABCD-proteins, ACOX1), leading to accumulation of acyl-carnitines, and decreased ATP production compared with wild-type (WT) cells.
Coelho et al. (Wed,) studied this question.