Talasz, H. | Search bioRxiv

bioRxiv2024

Mitochondrial cardiolipin metabolism controlled by tafazzin enables ferroptosis

Mitochondria are important producers of reactive oxygen species, which are involved in triggering ferroptosis, a lipid peroxidation driven form of cell death. Paradoxically, in the rare inherited metabolic disease Barth Syndrome, we discovered a protection from erastin-induced ferroptosis, despite intrinsically elevated mitochondrial ROS levels. The affected transacylase tafazzin, which is mutated in Barth Syndrome, is pivotal for remodeling of the dimeric phospholipid cardiolipin. They unique to mitochondria and essential for shaping their membrane functionalities. We investigated which downstream effects of the pathogenic membrane alterations are responsible for the protective effect against ferroptosis. We found that while iron metabolism, the unsaturation of membrane lipids, and the metabolic activity of the cells were modifying factors, they were not causal. However, we observed that cardiolipin abnormalities are not limited to impair only inner, but also outer mitochondrial membrane protein complexes. Specifically, they impact abundance and oligomerization of voltage-dependent anion channels (VDAC) in response to oxidative stress. We found that tafazzin deficiency via alteration of cardiolipins affects VDAC functionality, thereby modulating small molecule transport and signaling between mitochondria and the remaining cell. This is in line with a reduction of mitochondria-associated membranes (MAM) sites that are formed through VDACs and trapping ROS in mitochondria where they are unable to contribute to ferroptosis. These findings demonstrate that the mitochondrial membrane architecture impacting on subcellular small molecule distribution crucially impact on the manifestation of cell fate decisions, including ferroptosis.

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↗