Rueda, M. P. C. | bioRxiv Science

bioRxiv2024

Stomatin-like protein 2 senses oxidative stress through the interaction with phosphatidic acid to promote mitochondrial unfolded protein response

The mitochondrial unfolded protein response (mtUPR) is an essential mechanism that maintains mitochondrial fitness during stress. Using a genetic screen in Caenorhabditis elegans looking for regulators of the mtUPR, we identified stl-1, an ortholog of human Stomatin-like protein 2 (SLP-2), as a positive regulator in healthy mitochondria. The loss of STL-1 and SLP-2 results in an impaired mtUPR in C. elegans and human cells, respectively. Both C. elegans STL-1 and human SLP-2 are proteins located at the inner mitochondrial membrane and exhibit strong lipid binding affinity to phosphatidic acid. Oxidative stress alters the STL-1 localization within the mitochondrial membrane, and triggers the mtUPR dependent on both STL-1/SLP-2 and mitochondrial PA homeostasis. These results reveal an evolutionarily conserved mechanism of mitochondrial protection, in which STL-1/SLP-2 acts as a sensor for changes in mitochondrial membrane lipid composition through physical interaction with PA species, thereby mediating the mtUPR and enhancing stress resistance.

molecular biology↗

bioRxiv2023

Dopamine-iron homeostasis interaction rescues mitochondrial fitness in Parkinson's disease

Imbalances of iron and dopamine metabolism along with mitochondrial dysfunction have been linked to the pathogenesis of Parkinsons disease (PD). We have previously suggested a direct link between iron homeostasis and dopamine metabolism, as dopamine can increase cellular uptake of iron into macrophages thereby promoting oxidative stress responses. In this study, we investigated the interplay between iron, dopamine, and mitochondrial activity in neuroblastoma SH-SY5Y cells and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons differentiated from a healthy control and a PD patient with a mutation in the -synuclein (SNCA) gene. In SH-SY5Y cells, dopamine treatment affected the expression of transmembrane iron transporters and cellular iron accumulation. Furthermore, dopamine supplementation led to decreased mitochondrial respiration and reduced mitochondrial fitness, including reduced mtDNA copy number and citrate synthase activity, increased oxidative stress and impaired aconitase activity. In dopaminergic neurons derived from a healthy control individual, dopamine showed comparable effects as observed in SH-SY5Y cells. The hiPSC-derived PD neurons harboring an endogenous SNCA mutation demonstrated altered mitochondrial iron homeostasis, reduced mitochondrial capacity along with increased oxidative stress and alterations of tricarboxylic acid cycle linked metabolic pathways compared with control neurons. Importantly, dopamine treatment of these PD neurons promoted a rescue effect by increasing mitochondrial respiration, activating antioxidant stress response, and normalizing altered metabolite levels linked to mitochondrial function. These observations provide evidence that dopamine affects iron homeostasis, intracellular stress responses and mitochondrial function in healthy cells, while dopamine supplementation can restore this disturbed regulatory network in PD cells.

neuroscience↗