Review
Mitochondrial Dynamics and Metabolic Regulation

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Mitochondrial morphology varies widely across different cell types and tissues and results from the opposing and coordinated forces of mitochondrial fission and fusion of OMs and IMs.

The regulation of fusion and fission is manifold and responds rapidly to metabolic cues.

The fusion and fission machinery is essential for life, and genetic ablation of individual components in adult tissues impairs organ function and whole-body metabolism.

Interpreting the relevance of mitochondrial morphology is complicated by the functional redundancy and additional roles that these components have within as well as outside mitochondria.

Mitochondrial morphology varies tremendously across cell types and tissues, changing rapidly in response to external insults and metabolic cues, such as nutrient status. The many functions of mitochondria have been intimately linked to their morphology, which is shaped by ongoing events of fusion and fission of outer and inner membranes (OM and IM). Unopposed fission causes mitochondrial fragmentation, which is generally associated with metabolic dysfunction and disease. Unopposed fusion results in a hyperfused network and serves to counteract metabolic insults, preserve cellular integrity, and protect against autophagy. Here, we review the ways in which metabolic alterations convey changes in mitochondrial morphology and how disruption of mitochondrial morphology impacts cellular and organismal metabolism.

Section snippets

Mitochondria Forms and Functions

The need for mitochondria in healthy tissues is ubiquitous, yet the emphasis placed on the various metabolic functions they perform varies across tissues. The morphology of mitochondria is inextricably linked to its functions, which include the production of ATP by oxidative phosphorylation (OXPHOS; see Glossary), regulation of programmed cell death, calcium homeostasis, and the generation and control of reactive oxygen species (ROS) [1]. Balanced fusion and fission events shape mitochondria to

The Molecular Machinery of Mitochondrial Dynamics

With pioneering studies in yeast leading the way, the past 15 years of research have identified the machinery of mitochondrial fusion and fission (Figure 2). Mechanistic insight into the physiological relevance of mitochondrial dynamics has come from the study of patients harboring genetic lesions in components of either fusion (MFN2 and OPA1) or fission (Dynamin-related protein 1; DRP1) [5], which cause mitochondrial fragmentation and hypertubulation, respectively. We first introduce critical

Mitofusins

Dynamin-like GTPases mediate the fusion of both mitochondrial OMs and IMs. The mammalian orthologs mitofusin 1 and mitofusin 2 (Mfn1 and Mfn2) orchestrate OM fusion and are required for the maintenance of a reticular mitochondrial network in cells [6]. Both proteins contain conserved catalytic GTP-binding domains at the N termini and are anchored to the OM by C-terminal transmembrane domains (Figure 2). Mitofusins mediate OM fusion by homo- and heterotypic interactions that depend on GTP

L-OPA1

Optic atrophy 1 (OPA1) is a dynamin-like GTPase anchored to the IM by an N-terminal transmembrane domain. The bulk of the protein, including the GTP-binding and GTPase effector domains, is exposed to the IM space (IMS). Multiple forms of OPA1 are found in mammalian cells and tissues, which are the result of alternative splicing and proteolytic cleavage (Figure 3, Key Figure). Alternative splicing of OPA1 gives rise to long forms (L-OPA1; denoted a and b) that are proteolytically cleaved to

DRP1

DRP1 performs outer membrane fission. It mediates mitochondrial fission in response to specific cellular signals that cause its translocation from the cytosol to the OM, where it oligomerizes into ring-like structures at future sites of division. Several DRP1 receptors and recruitment factors on the OM have been identified, including FIS1, MFF, MiD49, and MiD51, which exert partially overlapping functions [24]. Putative mitochondrial fission sites marked by the endoplasmic reticulum (ER) and

Fission Machinery of the Inner Membrane

Our understanding of OM fission has advanced greatly since the discovery of DRP1 and its receptors, but less is understood about how the IM divides. Whether DRP1-mediated constriction of the OM alone is sufficient to concomitantly drive IM scission or whether additional machinery at the IM is required remains unclear. Two IM proteins, S-OPA1 and MTP18, were proposed to have important roles in mitochondrial fission and may turn out to be part of the fission machinery in the IM.

Metabolic Regulation of Mitochondrial Dynamics

Mitochondrial morphology is dynamic and sensitive to metabolic alterations [42]. Mitochondrial fusion is positively associated with increased ATP production, while inhibition of fusion is associated with impaired OXPHOS, mtDNA depletion, and ROS production [2]. The balance of fission and fusion can be tipped in either direction by changes in nutrient availability and metabolic demands, causing mitochondria to become fragmented or hypertubular. In cultured cells, metabolic stress and starvation

Regulation of Metabolism by Mitochondrial Dynamics

Mitochondrial morphology varies tremendously across tissues of varying metabolic needs [55]. Within a given tissue, metabolic status can dramatically affect the form and function of mitochondria, which consequently influences the organ function. Conversely, genetic ablation of key components of mitochondrial fusion and fission cause metabolic changes that have been attributed to disturbed mitochondrial dynamics (see Outstanding Questions). Here, we summarize the evidence that mitochondrial

Concluding Remarks and Future Perspectives

The past decade has seen a growing number of studies of the machinery of mitochondrial fusion and fission in cellular and animal models, providing us with unassailable evidence for the critical roles these components have in organ development, function, and metabolism. Yet, the interpretation of these studies has been mired by functional redundancy and a pleiotropic array of mitochondrial and cellular dysfunctions, which results from the deletion of any one of these components. Do deficiencies

Glossary

Agouti-related peptide (AgRP)
a peptide produced by specific hypothalamic neurons; AgRP increases appetite and promotes feeding behavior while reducing energy expenditure.
Autosomal dominant optic atrophy (ADOA)
inherited bilateral degeneration of the optic nerve caused by mutations in Opa1 and the most common autosomally inherited optic atrophy.
Cardiolipin (CL)
a nonbilayer-forming phospholipid unique to mitochondria that is required for the optimal function of multiple enzymes at the IM and for

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