Lipid transfer between mitochondria and lipid droplets contributes to stress-induced mitochondrial hyperfusion

Thesis

Starvation triggers mitochondrial elongation, known as stress-induced mitochondrial hyperfusion (SIMH), which coincides with lipid droplet (LD) biogenesis and the formation of mitochondria-LD contact sites. The mechanisms coupling these processes remain unclear. MIGA2, a mitochondrial lipid transfer protein (LTP), forms contact sites with LDs and the endoplasmic reticulum (ER) via VAP A/B proteins. MIGA2 is also important for both mitochondrial elongation and LD biogenesis. In my thesis, I investigated the role of MIGA2 in LD biogenesis and in controlling SIMH.

I found that LD consumption by β-oxidation is not required for SIMH. My results instead show that triacylglycerol (TAG) synthesis and LD biogenesis are important for the morphological changes in mitochondria. Furthermore, I demonstrated that lipid transport by MIGA2 is critical in the starvation response, mediating both SIMH and metabolic adaptation and activation of cell survival.

I uncovered that release of MIGA2 from its interaction with VAPB in the ER is essential for SIMH and LD biogenesis. This interaction is under the control of phosphorylation of a serine rich motif (SRM), regulating LD targeting of MIGA2 which simultaneously stimulates SIMH and LD biogenesis. My results highlight the MIGA2-LD contact is central to controlling mitochondrial behaviour. Finally, we show through lipidomics and proteo-lipidomics experiments that MIGA2 facilitates the export of specific cardiolipin species from the mitochondria. A working model is that breakdown products of these cardiolipins called phosphatidic acids are transferred to the LD, where DGAT2 converts them into TAGs for storage. The net effect of this lipid species selective lipid transfer to the LD is an increased unsaturation of the inner mitochondrial membrane which activates cellular respiration. A block of the MIGA2 transport system renders SIMH defective and increases metabolic vulnerability during starvation. In summary, my DPhil thesis uncovers a novel molecular mechanism underpinning how lipid transport at membrane contact sites controls mitochondrial shape and function as a central part of cellular stress response. Future studies will explore how these morphological changes exactly impact mitochondrial activity. More broadly, this work underscores the significance of non-vesicular lipid trafficking in the functional remodelling of organelle behaviour and activity during stress.

Authors: Saukko-Paavola, A

• DOI: 10.5287/ora-gpngvk8k4
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: lipid droplets; mitochondria; stress responses; lipid metabolism; membrane contact sites
• Subjects: Cell Biology; Molecular biology