Organelle interplay in cell metabolism and neuron function

Organelles serve to compartmentalize eukaryotic cells, thereby creating specialized environments for different, sometimes competing cellular processes. Contact sites between organelles enable the exchange of material such as lipids and signaling molecules. Contact sites are present between all organelles, but best understood are the contacts between the endoplasmic reticulum (ER) and the mitochondrion. The functions of ER-mitochondria contacts are manifold: they serve the exchange of phospholipids and calcium ions, and the formation of these contacts is a prerequisite for mitochondrial quality control. Fragmentation of mitochondria is required for their degradation, and the proteins that execute the fission of mitochondria bind at ER-mitochondria contact sites. In addition, ER membranes wrap around the fission site during fragmentation. ER-mitochondria communication is notably disturbed in neurodegenerative diseases like Parkinson’s disease (PD). 
We try to understand how ER-mitochondria communication affects the function and physiology of neurons, and how this affects the organism’s physiology. We could show that the exchange of phospholipids between ER and mitochondria regulates mitochondrial dynamics and activity in dopaminergic neurons. We found that in mutants for the ER protein Creld, ER-mitochondria communication is impaired, resulting in low production of the reactive oxygen species hydrogen peroxide. We suggest that this leads to inactivity of dopaminergic neurons, resulting in a strong, PD-like locomotion deficit. Moreover, we show that cells react to low activity of the mitochondrial respiratory complex I by increasing ER-mitochondria contacts (Paradis M, Kucharowski N, Edwards Faret G, Maya Palacios SJ, Meyer C, Stümpges B, Jamitzky I, Kalinowski J, Thiele C, Bauer R, Paululat A, Sellin J, Bülow MH. The ER protein Creld regulates ER-mitochondria contact dynamics and respiratory complex 1 activity. Sci Adv. 2022 Jul 22;8(29):eabo0155. doi: 10.1126/sciadv.abo0155.)   

Peroxisomes are probably the least well understood organelles, and many of their functions have yet to be determined. Peroxisomes are important regulators of the cell’s lipid metabolism and redox balance. They have been reported to accumulate at ER-mitochondria contact sites. A well-known consequence of peroxisome dysfunction is the accumulation of very-long-chain fatty acids. We showed previously that a metabolically more severe consequence is a shortage in medium-chain fatty acids. This shortage induces a signaling network that causes lipotoxicity and mitochondrial damage, which is ultimately fatal. By dietary supplementation with medium-chain fatty acids, we can rescue the lethality of mutants without functional peroxisomes (Bülow MH, Wingen C, Senyilmaz D, Gosejacob D, Sociale M, Bauer R, Teleman AA, Hoch M, Sellin S. Unbalanced lipolysis resulting in lipotoxicity provokes mitochondrial damage in peroxisome-deficient Pex19 mutants. Mol Biol Cell. 2018 Feb 15;29(4):396-407 and Sellin J, Wingen C, Gosejacob D, Senyilmaz D, Hänschke L, Büttner S, Meyer M, Bano D, Nicotera P, Teleman AA and Bülow MH. Dietary rescue of lipotoxicity-induced mitochondrial damage in Peroxin19 mutants. PLOS Biol 16(6): e2004893 June 19, 2018). A major component of the signaling network that we identified as the underlying cause for the aberrant metabolism following peroxisome loss and medium-chain fatty acid shortage is Lipase 3, which is a putative phospholipase with a role in linking the nutritional status to aging (Hänschke L, Heier C, Maya Palacios SJ, Özek HE, Thiele C, Bauer R, Kühnlein RP and Bülow MH. Drosophila Lipase 3 Mediates the Metabolic Response to Starvation and Aging. Front Aging 2022 3:800153. doi: 10.3389/fragi.2022.800153). Our current research focuses on the role of peroxisomes in the secretion of neuropeptides.