Trends in Cell Biology
ReviewMitochondria: from cell death executioners to regulators of cell differentiation
Section snippets
Mitochondrial morphology and cell biology
From a purely mitochondria-centric point of view, mitochondria can be regarded as the crucial organelles in determining cell fate. Indeed, whether a cell lives or dies depends on mitochondria. Not only do they participate in numerous essential biosynthetic and metabolic pathways, as well as in calcium and redox homeostasis, but they are also key regulators of apoptosis 1, 2, 3.
Mitochondria continually fuse and divide, and their quality, distribution, size, and motility are finely tuned 4, 5.
Regulators of mitochondrial shape
The double membrane-bound architecture of mitochondria is regulated and maintained by a family of ‘mitochondria-shaping’ proteins. Mitochondrial fusion is mediated by the dynamin-related GTPases Mitofusin (MFN) 1 and 2, and by Optic Atrophy 1 (OPA1) (Figure 1A) (see Glossary). MFN1 and MFN2 fuse the outer mitochondrial membrane (OMM). They form homo- and hetero-dimers that undergo conformational changes upon GTP hydrolysis in order to effect OMM fusion 8, 9. In addition to serving as key
Mitochondrial morphology and cell stress
In order for an apoptotic signal to induce cell death, several changes must occur in mitochondria including mitochondrial fragmentation, cristae remodeling and mitochondrial outer membrane permeabilization (MOMP). These changes culminate in the release of cytochrome c and other pro-apoptotic factors, such as serine protease OMI/HtrA2, Smac/Diablo, endonuclease G, and apoptosis inducing factor (AIF), ultimately triggering caspase activation and cell death [6]. Therefore, it is not surprising
Mitochondrial morphology in development and differentiation
Given the importance of mitochondria in intermediate metabolism, they have been regarded as key suppliers of the ATP required for development and differentiation. Not surprisingly, defects in embryogenesis and in tissue differentiation and development caused by gene disruption experiments of mitochondria shaping proteins in the mouse have been interpreted as the consequence of impaired bioenergetics or apoptosis 8, 67, 68. Loss of Mfn2, but not Mfn1 causes severe defects in the placental
Concluding remarks
The core components of the mammalian mitochondrial fusion–fission machinery have been identified, and growing evidence suggests that mitochondrial morphology regulates apoptosis, ER-communication, autophagy, neurodegenerative disorders, and cancer [101]. The recent discoveries that mitochondria are not only targets of nuclear signaling cascades, but also influencers of these pathways to define the differentiation program of stem cells in vitro and in vivo, adds a novel layer of complexity to
Acknowledgments
L.S. is a Senior Scientist of the Dulbecco Telethon Institute. Research in his laboratory is supported by Telethon Italy GGP12162, GPP10005, AIRC Italy, ERC ERMITO, FP7 CIG CristOpa, and MIUR FIRB Automed.
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