Trends in Endocrinology & Metabolism
ReviewMitochondrial Dynamics and Metabolic Regulation
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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