Trends in Immunology
ReviewSeries: ImmunometabolismMitochondrial Dynamics at the Interface of Immune Cell Metabolism and Function
Section snippets
Metabolic Shifts during Immune Responses
For an immune response to proceed, specialized cells of the immune system morph from a state of relative quiescence to one of high activity. A prime example of a cell type that undergoes this transformation is the T lymphocyte. Initially patrolling our body as quiescent naïve T cells, these cells become rapidly activated upon antigen detection to T effector (Teff) cells that proliferate, secrete cytokines, and migrate to the sites of infection. Once the antigen load is reduced, and supportive
Mitochondrial Metabolism and Its Cellular Function
Mitochondria are characterized by a complex architecture and high degree of compartmentalization that are crucial for their function. They are composed of an outer mitochondrial membrane (OMM), and a heavily folded inner mitochondrial membrane (IMM), the site of the electron transport chain (ETC). Historically, the major role of mitochondria was thought to be to the efficient coupling of substrate oxidation through the TCA cycle to ATP production by the ETC. In fact, mitochondria produce up to
Mitochondrial Fission and Fusion Dynamics
For a long time mitochondria were viewed as isolated and static organelles, until advances in live cell imaging and genetic screening revealed that mitochondria are highly dynamic. Not only can mitochondria, driven by cytoskeletal transport, change their position inside cells but their architecture is also continuously modulated by fission and fusion reactions. In recent years these mitochondrial shape-changes, referred here to as ‘mitochondrial dynamics’, have gained substantial attention
The Mitochondrial Fission Machinery
Mitochondrial fission is regulated by the GTPase dynamin-related protein 1 (Drp1) that drives division at specific points along mitochondria. These sites are pre-marked by the endoplasmic reticulum (ER) [18] and actin 19, 20, allowing Drp1 to assemble into oligomeric spirals that constrict and finally pinch the mitochondrion apart. The final separation step proceeds via cooperation between Drp1 and dynamin 2 [21]. Because most cellular Drp1 is not constitutively associated with mitochondrial
The Mitochondrial Fusion Machinery
Mitochondrial fusion is a two-step process where OMM fusion is followed by fusion of the IMM. The mitochondrial fusion machinery consists of three dynamin family GTPases, mitofusin (Mfn) 1 and 2 on the OMM and optic atrophy protein 1 (Opa1) on the IMM 29, 30, 31. The exact mechanism of how Mfns mediate the fusion of the OMM is not clear, but several lines of evidence support a mechanism whereby Mfn1 and Mfn2 interact with their C-termini in trans between neighboring mitochondria, thus promoting
Mitochondrial Dynamics as a Driver for Metabolic Cell States
In several immune cells, including T cells, macrophages, and mast cells, mitochondria have been shown to adapt specific mitochondrial morphologies according to the cellular activation state 40, 41, 42. Emerging evidence now also highlights that the ablation of fission and fusion proteins impacts on immune cell metabolism and function. These findings complement studies in metabolic tissues, such as the liver and the nervous system, where altered fission/fusion dynamics cause defects in cell
Metabolism as a Driver for Mitochondrial Fission and Fusion Dynamics
While genetic studies are beginning to reveal mitochondrial dynamics as a crucial regulator of immune metabolism and function, our insights into the mechanistic regulation of this process are still developing. In non-immune cells, several regulatory layers control the fission/fusion core machinery from the transcriptional to the post-translational level [63]. This includes orchestration of fission/fusion activities by metabolic cues 64, 65. In the next paragraphs we summarize the evidence for
Concluding Remarks and Future Directions
In this review we have summarized recent exciting findings on how mitochondrial dynamics and metabolism are interlinked to shape immune cell function and fate. In recent years a growing number of studies have highlighted that mitochondria can acquire immune-stage specific morphologies. Preventing immune cells from reaching such states had dramatic consequences, impairing their metabolic reprogramming and/or the acquisition of specific functions. While our insight is still limited to only a few
Glossary
- Apoptosis
- programmed cell death.
- Autophagy
- a process that depends on the de novo formation of a double-membrane enclosed organelle, the autophagosome, that is able to engulf cytosolic material and target it for lysosomal degradation.
- Cristae
- the folds of the inner mitochondrial membrane.
- Electron transport chain (ETC)
- at the inner mitochondrial membrane (IMM) four complexes (I–IV) transfer electrons from electron donors to acceptors to produce an electrochemical proton gradient across the IMM.
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