Abstract
<jats:p> Peroxiredoxin 6 (PRDX6) is a multifunctional enzyme with peroxidase, calcium independent phospholipase A2 (aiPLA₂) and lysophospatidylcholine acyltransterase (LPCAT) activities. Although PRDX6 can repair peroxidised phospholipids and help prevent ferroptosis, its role in the adaptive response to physiological oxidative stress remains unclear. In this study PRDX6 function was investigated using myoblasts exposed to an acute low concentration of H <jats:sub>2</jats:sub> O <jats:sub>2</jats:sub> and <jats:italic>Caenorhabditis elegans</jats:italic> subjected to a swimming intervention. Mild oxidative stress promoted myogenesis and mitochondrial turnover in myoblasts, while exercise enhanced activity and longevity in <jats:italic>C. elegans</jats:italic> . The adaptive responses were associated with increased mitochondrial localisation of PRDX6. In contrast, loss of PRDX6 under mild stress conditions resulted in increased mitochondrial lipid peroxidation, enhanced mitochondrial ER contact sites (MERCS), mitochondrial calcium accumulation, release of mitochondrial DNA and activation of innate immune signalling pathways. Similar phenotypes were induced by the ferroptosis activator erastin and rescued by the lipid peroxyl scavenger Ferrostatin-1, indicating lipid peroxidation was the key triggering event. Furthermore, inhibition of mitochondrial calcium uptake in <jats:italic>C. elegans</jats:italic> prevented calcium overload and attenuated inflammatory signalling. Together, the results identify PRDX6 as a conserved regulator of mitochondrial adaptation to physiological oxidative stress, functioning to limit mitochondrial lipid peroxidation and prevent excessive MERCS assembly, mitochondrial calcium dysregulation and inflammatory activation. </jats:p>