Owing to their ability to efficiently generate ATP required to sustain normal cell function, mitochondria are often considered the 'powerhouses of the cell'. However, our understanding of the role of ...mitochondria in cell biology recently expanded when we recognized that they are key platforms for a plethora of cell signalling cascades. This functional versatility is tightly coupled to constant reshaping of the cellular mitochondrial network in a series of processes, collectively referred to as mitochondrial membrane dynamics and involving organelle fusion and fission (division) as well as ultrastructural remodelling of the membrane. Accordingly, mitochondrial dynamics influence and often orchestrate not only metabolism but also complex cell signalling events, such as those involved in regulating cell pluripotency, division, differentiation, senescence and death. Reciprocally, mitochondrial membrane dynamics are extensively regulated by post-translational modifications of its machinery and by the formation of membrane contact sites between mitochondria and other organelles, both of which have the capacity to integrate inputs from various pathways. Here, we discuss mitochondrial membrane dynamics and their regulation and describe how bioenergetics and cellular signalling are linked to these dynamic changes of mitochondrial morphology.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Permanent residency in the eukaryotic cell pressured the prokaryotic mitochondrial ancestor to strategize for intracellular living. Mitochondria are able to autonomously integrate and respond to ...cellular cues and demands by remodeling their morphology. These processes define mitochondrial dynamics and inextricably link the fate of the mitochondrion and that of the host eukaryote, as exemplified by the human diseases that result from mutations in mitochondrial dynamics proteins. In this review, we delineate the architecture of mitochondria and define the mechanisms by which they modify their shape. Key players in these mechanisms are discussed, along with their role in manipulating mitochondrial morphology during cellular action and development. Throughout, we highlight the evolutionary context in which mitochondrial dynamics emerged and consider unanswered questions whose dissection might lead to mitochondrial morphology-based therapies.
Mitochondrial architecture is involved in several functions crucial for cell viability, proliferation, senescence, and signaling. In particular, mitochondrial dynamics, through the balance between ...fusion and fission events, represents a central mechanism for bioenergetic adaptation to metabolic needs of the cell. As key regulators of mitochondrial dynamics, the fusogenic mitofusins have recently been linked to mitochondrial biogenesis and respiratory functions, impacting on cell fate and organism homeostasis. Here we review the implication of mitofusins in the regulation of mitochondrial metabolism, and their consequence on energy homeostasis at the cellular and physiological level, highlighting their crucial role in metabolic disorders, cancer, and aging.
Schrepfer and Scorrano review the role of the outer mitochondrial fusion protein mitofusins in the regulation of mitochondrial and cellular metabolism. They provide an up-to-date picture of the involvement of these proteins in a variety of cellular processes not limited to mitochondrial function and morphology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Highlights • Mitochondrial morphology controls mitochondrial function. • Mitochondrial shape controls signaling cascades and cell fate. • Mitochondrial dynamics and function direct development and ...differentiation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Mitochondria are key organelles in the regulation of apoptosis induced by intrinsic stimuli. This is accomplished by the release in the cytoplasm of cytochrome
c and of other cofactors that ensure ...the activation of effector caspases. Multiple changes in the shape of the organelle occur around the time of the release of these factors, including fragmentation of the mitochondrial network and the activation of the so-called “cristae remodeling” pathway. However, contrasting evidence exist on the functional role of these changes. Here we review the molecular mechanisms that control mitochondrial shape, their changes during apoptosis and the role that these changes might play in the amplification of the apoptotic cascade.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Mitochondrial cristae are dynamic bioenergetic compartments whose shape changes under different physiological conditions. Recent discoveries have unveiled the relation between cristae shape and ...oxidative phosphorylation (OXPHOS) function, suggesting that membrane morphology modulates the organization and function of the OXPHOS system, with a direct impact on cellular metabolism. As a corollary, cristae-shaping proteins have emerged as potential modulators of mitochondrial bioenergetics, a concept confirmed by genetic experiments in mouse models of respiratory chain deficiency. Here, we review our knowledge of mitochondrial ultrastructural organization and how it impacts mitochondrial metabolism.
Mitochondria adapt their shape to sustain necessary cellular functions.
Cristae are functional dynamic compartments whose shape and dimensions modulate the kinetics of chemical reactions and the structure of protein complexes.
Cristae shape is maintained by the cooperation of mitochondrial-shaping proteins.
Perturbations of mitochondrial-shaping proteins disrupt cristae shape and affect the structure of the OXPHOS system, impairing cellular metabolism and growth.
Cristae shape could be an interesting and promising therapeutic target for modulating metabolic dysfunction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The interface between mitochondria and the endoplasmic reticulum is emerging as a crucial hub for calcium signalling, apoptosis, autophagy and lipid biosynthesis, with far reaching implications in ...cell life and death and in the regulation of mitochondrial and endoplasmic reticulum function. Here we review our current knowledge on the structural and functional aspects of this interorganellar juxtaposition. This article is part of a Special Issue entitled: Calcium Signaling In Health and Disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.
•Mitochondria and ER are tethered.•Tethering controls multiple mitochondrial and ER functions.•Molecules involved in tethering are being discovered and characterized.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Close proximities between organelles have been described for decades. However, only recently a specific field dealing with organelle communication at membrane contact sites has gained wide ...acceptance, attracting scientists from multiple areas of cell biology. The diversity of approaches warrants a unified vocabulary for the field. Such definitions would facilitate laying the foundations of this field, streamlining communication and resolving semantic controversies. This opinion, written by a panel of experts in the field, aims to provide this burgeoning area with guidelines for the experimental definition and analysis of contact sites. It also includes suggestions on how to operationally and tractably measure and analyze them with the hope of ultimately facilitating knowledge production and dissemination within and outside the field of contact-site research.
Mitochondria are highly dynamic organelles, the location, size and distribution of which are controlled by a family of proteins that modulate mitochondrial fusion and fission. Recent evidence ...indicates that mitochondrial morphology is crucial for cell physiology, as changes in mitochondrial shape have been linked to neurodegeneration, calcium signalling, lifespan and cell death. Because immune cells contain few mitochondria, these organelles have been considered to have only a marginal role in this physiological context—which is conversely well characterized from the point of view of signalling. Nevertheless, accumulating evidence shows that mitochondrial dynamics have an impact on the migration and activation of immune cells and on the innate immune response. Here, we discuss the roles of mitochondrial dynamics in cell pathophysiology and consider how studying dynamics in the context of the immune system could increase our knowledge about the role of dynamics in key signalling cascades.
Accumulating evidence shows that mitochondrial dynamics impact on the migration and activation of immune cells and on the innate immune response. This Review addresses the roles of mitochondrial dynamics in cell patho‐physiology and considers the role dynamics may play in key signaling cascades.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Controlled changes in mitochondrial morphology participate in cellular signaling cascades. However, the molecular mechanisms modifying mitochondrial shape are largely unknown. Here we show that the ...mitogen-activated protein (MAP) kinase cascade member extracellular-signal-regulated kinase (ERK) phosphorylates the pro-fusion protein mitofusin (MFN) 1, modulating its participation in apoptosis and mitochondrial fusion. Phosphoproteomic and biochemical analyses revealed that MFN1 is phosphorylated at an atypical ERK site in its heptad repeat (HR) 1 domain. This site proved essential to mediate MFN1-dependent mitochondrial elongation and apoptosis regulation by the MEK/ERK cascade. A mutant mimicking constitutive MFN1 phosphorylation was less efficient in oligomerizing and mitochondria tethering but bound more avidly to the proapoptotic BCL-2 family member BAK, facilitating its activation and cell death. Moreover, neuronal apoptosis following oxygen glucose deprivation and MEK/ERK activation required an intact MFN1T562. Our data identify MFN1 as an ERK target to modulate mitochondrial shape and apoptosis.
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•Mfn1 is phosphorylated by ERK to inhibit mitochondrial fusion•Mfn1 phosphorylation stimulates mitochondrial permeabilization and apoptosis•The MAPK cascade regulates mitochondrial shape and apoptosis via Mfn1
Pyakurel et al. show that the pleiotropic ERK kinase phosphorylates the mitochondrial fusion protein Mitofusin 1. Phosphorylation by ERK inhibits mitochondrial fusion and stimulates apoptotic mitochondrial permeabilization, identifying how mitochondrial shape and apoptosis
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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