Keeping mitochondria and ER together: a matter of life, death and neurodegeneration (349.2)

Abstract

Mitochondrial ultrastructural and morphological changes have been implied in the control of several physiological and pathological changes, including apoptosis. However, the role of mitochondrial dynamics in the control of complex cellular cues and in response to reversible and irreversible cellular damage is not clarified. Today we will overview the key experiments that shed light on the role of mitochondrial shape and ultrastructure in cell physiology and we will present our recent data obtained in genetic models of ablation and up‐regulation of the key mitochondrial shaping proteins Optic atrophy 1 (Opa1) and mitofusin in the mouse and in embryonic stem cells. The in vivo experiments of tissue damage by inducing atrophy, apoptosis or ischemia/reperfusion indicate that the master cristae biogenetic regulator Opa1 can prevent multiple forms of tissue damage by controlling mitochondrial cytochrome c release and metabolic efficiency. Ablation of Mitofusin 1 and 2 in the embryonic mouse heart, or gene‐trapping of Mitofusin 2 or Opa1 in mouse embryonic stem cells (ESCs), arrested mouse heart development and impaired differentiation of ESCs into cardiomyocytes. Gene expression profiling revealed roles for TGFβ/BMP, SRF, GATA4, and Mef2 differentiation factors, linked to increased Notch1 activity that, unexpectedly downstream of the Ca2+‐dependent phosphatase calcineurin, impaired ESC differentiation. Orchestration of cardiomyocyte differentiation by mitochondrial morphology reveals how mitochondria, Ca2+ and calcineurin interact to regulate Notch1 signaling. Thus, mitochondrial shape and ultrastructure dictate organelle function and complex tissue responses.