Trends in Cell Biology
Volume 24, Issue 12, December 2014, Pages 761-770
Journal home page for Trends in Cell Biology

Review
Mitochondria: from cell death executioners to regulators of cell differentiation

https://doi.org/10.1016/j.tcb.2014.08.005Get rights and content

Highlights

  • Mitochondrial morphology controls mitochondrial function.

  • Mitochondrial shape controls signaling cascades and cell fate.

  • Mitochondrial dynamics and function direct development and differentiation.

Most, if not all mitochondrial functions, including adenosine-5′-triphosphate (ATP) production and regulation of apoptosis and Ca2+ homeostasis, are inextricably linked to mitochondrial morphology and dynamics, a process controlled by a family of GTP-dependent dynamin related ‘mitochondria-shaping’ proteins. Mitochondrial fusion and fission directly influence mitochondrial metabolism, apoptotic and necrotic cell death, autophagy, muscular atrophy and cell migration. In this review, we discuss the recent evidence indicating that mitochondrial dynamics influence complex signaling pathways, affect gene expression and define cell differentiation. These findings extend the importance of mitochondria to developmental biology, far beyond their mere bioenergetic role.

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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