Tying Trafficking to Fusion and Fission at the Mighty Mitochondria

Abstract

The mitochondrion is a unique organelle that serves as the main site of adenosine triphosphate (ATP) generation needed for energy in the cell. However, mitochondria also play essential roles in cell death through apoptosis and necrosis, as well as a variety of crucial functions related to stress regulation, autophagy, lipid synthesis, and calcium storage. There is a growing appreciation that mitochondrial function is regulated by the dynamics of its membrane fusion and fission; longer, fused mitochondria are optimal for ATP generation, whereas fission of mitochondria facilitates mitophagy and cell division. Despite the significance of mitochondrial homeostasis for such crucial cellular events, the intricate regulation of mitochondrial fusion and fission is only partially understood. Until very recently, only a single mitochondrial fission protein had been identified. Moreover, only now have researchers turned to address the upstream machinery that regulates mitochondrial fusion and fission proteins. Herein, we review the known GTPases involved in mitochondrial fusion and fission, but also highlight recent studies that address the mechanisms by which these GTPases are regulated. In particular, we draw attention to a substantial new body of literature linking endocytic regulatory proteins, such as the retromer VPS35 cargo selection complex subunit, to mitochondrial homeostasis. These recent studies suggest that relationships and cross-regulation between endocytic and mitochondrial pathways may be more widespread than previously assumed.

Graphical Abstract

1. Introduction

Mitochondria are well-known for the generation of cellular ATP via oxidative phosphorylation, but also have a significant role in regulating a variety of key cellular events including reactive oxygen species generation and sequestration ¹, calcium signaling ^2,3, apoptosis ⁴, iron homeostasis ^5,6, and cellular aging ^7,8. Mitochondrial function is highly regulated by the dynamics of this unique organelle that continuously undergoes sequential rounds of fusion and fission, a process that is essential for not only the mitochondrial homeostasis and health, but also the well-being of the entire cell.

Given the major role that mitochondria play in a cell’s overall fitness, it is not surprising to find that mitochondrial dysfunction, caused by impairment of either the fusion or fission process, ultimately results in a variety of pathologies including neurodegenerative diseases, cardiovascular diseases, and metabolic diseases ⁹. Despite recent advances and the identification of new proteins involved in mitochondrial homeostasis, many questions concerning the mechanisms by which these molecules influence mitochondria remain unresolved. Here we examine the established proteins involved in the regulation of mitochondrial fusion and fission, and highlight the role of several proteins that were recently implicated in these processes. In particular, the retromer complex subunits and associated proteins are discussed, as well as new evidence detailing how they influence mitochondrial dynamics.

2. Mitochondrial homeostasis

Mitochondria are complex organelles that are encased by an outer mitochondrial membrane (OMM) and an inner mitochondrial membrane (IMM), which generates two compartments: the intermembrane space and the matrix. Under physiological conditions, the two membranes must constantly work in tandem and cooperate in serial rounds of fusion and fission, leading to a dynamic homeostatic system within the cell ¹⁰. This is especially important because mitochondrial morphology has physiological significance; mitochondrial function depends on the dynamic nature and continuous yin-yang relationship between fusion and fission.

Although both fusion and fission are crucial to homeostasis and mitochondrial function, each process serves different roles in controlling mitochondrial function. Mitochondrial fusion, which results in the elongation of mitochondrial structures, leads to an increase in ATP production, and the transfer of mitochondrial material, such as various metabolites, to newly fused mitochondria ^11,12. Fusion events may be especially important under stress and starvation conditions, where maximizing ATP production is crucial for survival ¹³. In comparison, mitochondrial fission allows for the generation of new, smaller mitochondria, which are easier to distribute between dividing cells during mitosis ¹⁴. Not only does fission produce mitochondria that are more mobile, it also generates mitochondria that are able to undergo mitophagy, which is key to mitochondrial turnover ^15,16.

Mitochondrial biogenesis and mitophagy, as controlled by fusion or fission, respectively, are highly regulated processes and highlight the dramatic influence that mitochondrial homeostasis has on the cell. Under normal circumstances, fusion and fission occur simultaneously and at approximately the same rate; accordingly, any change in the homeostatic balance due to cellular stimuli may result in elongated or fragmented mitochondria. The physiological significance of mitochondrial fusion and/or fission dysfunction is illustrated by the growing number of pathological conditions related directly to mitochondrial homeostasis (Table 1) ^17,18.

Table 1.

Partial list of common mitochondrial-associated diseases related to fusion or fission.

Disorder	Characteristics	Altered Proteins or Genes	Mitochondrial Impact
Alzheimer’s Disease	Neuronal death in cerebral cortex	APP, Presenilin	Decrease in fusion and increase in fission 43,90,91
Parkinson’s Disease	Degeneration of dopaminergic neurons	Pink1, DJ-1, Parkin, VPS35	Enhanced mitochondrial fission, decrease in electron transport chain, increase in oxidative stress, decrease in mitophagy 64,92,93
Charcot-Marie-Tooth type 2A	Affects distal extremity sensory and motor neurons	Mfn2	Decrease in fusion 94–96
Autosomal dominant optic atrophy	Degeneration of retinal ganglia cells	OPA1	Decrease in fusion 33,97,98
Cardiomyocyte hypertrophy	Abnormal enlargement or thickening of the heart muscle	Drp1	Increase in fission 44,45,99
Type-2 Diabetes	Improper use of insulin that results in high blood glucose levels	Mfn2, ATP synthase	Decrease in fusion and decrease in ATP production 100–103

2.1 Role of mitochondrial homeostasis in disease

Mitochondrial disorders consist of a diverse group of diseases that are associated with mitochondrial dysfunction. Since mitochondria are semi-autonomous, they are comprised of proteins encoded by mitochondrial DNA (mtDNA), as well as proteins that are encoded by nuclear DNA (nDNA), and mutations in either set of genes may result in dysfunctional mitochondria. Indeed, mitochondria play vital functions in all nucleated cells, many of which are impacted by gene mutations in the form of primary or secondary mitochondrial-related diseases.

Primary mitochondrial diseases (PMD) are diseases that cause either complete or partial dysfunction of the mitochondrial electron transport chain due to mutations in mtDNA or nDNA that impair the biogenesis of proteins that facilitate oxidative phosphorylation ¹⁹. Secondary mitochondrial diseases (SMD) are illnesses in which there is a mitochondrial phenotype without identifiable mtDNA or nDNA mutations, or there are identifiable mutations whose clinical significance remains unknown ¹⁹. Moreover, by definition, SMD are caused by genes that influence environmental factors, and do not encode for proteins involved in production or regulation of oxidative phosphorylation ¹⁹.

Whether a mitochondrial disease primarily affects a specific organ(s) or body system varies with the given illness, but in most cases, the disease impacts cells/tissues/organs that require high levels of energy production and consumption, such as neuronal tissues, muscles, and the heart ²⁰. Just as there is wide variance in the range of tissues affected by mitochondrial diseases, the symptoms these diseases present with are broad and include neuropathies, myopathies, and cardiovascular disorders. Examples of some of the more common mitochondria-related diseases, their characteristics, the affected molecules, as well as the impact on mitochondria, are listed in Table 1. Many of these diseases result from a lack of balanced fission and fusion, resulting in mitochondria that are either dysfunctional or severely impaired. Although alterations in mitochondrial function are recognized as secondary contributors to the disease state, recent studies demonstrate that the implications of such dysfunction are crucial for disease progression ²¹. Despite a recent surge in the research of diseases associated with mitochondrial dysfunction, key mechanistic aspects underlying the physiology of impaired mitochondrial function remain poorly understood, highlighting the need for further research to support the development of novel therapeutics.

3. Direct Players in Mitochondrial Fusion and Fission

3.1 Effectors of Fusion

For two mitochondria to fuse together, two distinct fusion events need to occur between opposing mitochondria: 1) fusion between the OMM, and 2) fusion between the IMM. To date, three known mammalian GTPases have been associated with the process of mitochondrial fusion. Mitofusin-1 (Mfn1) and Mitofusin-2 (Mfn2) control fusion of the OMM, while the IMM is fused together by Optic Atrophy 1 (OPA1). The process of mitochondrial fusion is crucial for mitochondrial health, and blocked fusion results in a lack of membrane potential, and ultimately, impaired production of ATP ²². Fusion is also vital for the successful transfer of mitochondrial proteins and mtDNA to newly synthesized mitochondria, which helps prevent accumulation of mtDNA mutations and promotes normal mitochondrial function ²³.

3.1.1. Mitofusin-1 and Mitofusin-2

Mfn1 and Mfn2 serve similar functions, as both are responsible for the fusion of the OMM (Fig. 1), and are even interchangeable ²². Strikingly, despite their similarity and overlapping functions, and even though Mfn1 and Mfn2 are able to replace one another under certain circumstances, mutations in Mfn2 alone have significant physiological consequences and can result in neurodegenerative diseases such as Charcot-Marie-Tooth Neuropathy type 2A (Table 1) ^11,22. This suggests that cellular function is acutely attuned to OMM fusion, and that even minor disturbances in mitochondrial homeostasis can lead to significantly impaired mitochondrial function and disease. However, given the role of Mfn2 as an endoplasmic reticulum (ER)-mitochondrial tether ²⁴, Charcot-Marie-Tooth Neuropathy type 2A disease could potentially result from interference with ER-mitochondrial cross-talk.

Figure 1. Mitochondrial Fusion.

Mitochondria fusion via homotypic and heterotypic mitofusin interactions mediates OMM fusion, while OPA1 is responsible for IMM fusion events.

Mfn1 and Mfn2 are OMM transmembrane GTPases that contain several conserved domains, such as an amino-terminal GTP-binding domain, two coiled-coil domains, and a carboxyl-terminal with a bipartite transmembrane domain ²⁵. The difference between the Mfn1 and Mfn2 is that Mfn2 has an N-terminal Ras-binding domain that is lacking in Mfn1, suggesting that Mfn2 may have specific cellular functions that are not shared with Mfn1 ²⁶. The second coiled-coil domain of each protein is responsible for the tethering of the opposing mitochondria through a dimeric anti-parallel coiled-coil structure forming either homotypic or heterotypic dimers ²⁷. The precise mechanism by which mitofusin proteins promote fusion by dimerization of molecules on adjacent mitochondria is currently an active area of research.

3.1.2. Optic atrophy protein 1 (OPA1)

The major protein responsible for fusion of the IMM is OPA1 (Fig. 1). OPA1 has also been associated with functions such as cristae folding and apoptosis ^28,29. Whereas OPA1 function requires the presence of Mfn1, surprisingly Mfn2 is superfluous ³⁰. OPA1 is crucial for overall mitochondrial function, and its mutations can lead to Dominant Atrophy (DOA), an inherited disorder leading to optic nerve degeneration and the most common disease related to OPA1 ^31,32. Additional disorders caused by OPA1 mutations include ataxia, sensorineural deafness, and mitochondrial myopathy ^33–35.

For OPA1 to become activated once it has been transported to mitochondria, it must undergo proteolytic cleavage into two isoforms, known as the long and short forms ³⁶. The relative concentrations of the two isoforms under normal physiological conditions are nearly equal and are considered essential for proper OPA1 function in IMM fusion ³⁷. The long and short isoforms do not have any fusion function separately but must work in tandem to successfully mediate the fusion of the IMM ³⁸.

3.2 Effectors of Fission

Just as important as the mediators of mitochondrial fusion for homeostasis are the proteins that are responsible for mitochondrial membrane fission activity. Mitochondria are continuously executing a careful balancing act that, in addition to fusion, requires constant regulated division, termed mitochondrial fission. A long-acknowledged key player of mitochondrial fission is the GTPase, dynamin-related protein 1 (Drp1) ³⁹. However, more recently, researchers have discovered that an additional GTPase protein, dynamin-2 (Dyn2/Dnm2), directly coordinates mitochondrial fission with Drp1 ⁴⁰. While the GTPases are thought to provide the energy for fission from GTP hydrolysis, the process of fission requires a broader and more elaborate platform that involves other organelles such as the endoplasmic reticulum (ER), which helps initiate mitochondrial constriction prior to GTPase function. Fission events are crucial for mitochondrial remodeling and rearrangement within the cell or for their transfer to daughter cells following mitosis ⁴¹. Due to the importance of such events, subtle changes in the rate of mitochondrial fission can influence disease states such as Alzheimer’s disease ^42,43 and cardiomyocyte hypertrophy ^44,45.

3.2.1. ER/mitochondria contact sites

Contact sites exist between the ER and the mitochondria (Fig. 2) and studies have shown that these sites are crucial for phospholipid synthesis, calcium signaling, as well as for mitochondrial constriction to mark fission sites ^46,47. Indeed, there are several types of bridges that connect these two distinct organelles. For example, in yeast, a distinct structure termed the ER Mitochondria Encounter Structure (ERMES) is involved in mitochondrial fission, and in mammalian cells, Mfn2 is potentially responsible for such contact sites ^48,49. A more recent study has identified PDZD8, a structural and functional homolog of the yeast ERMES protein MMM1, as playing a key role in tethering mitochondria to the ER in mammalian neurons ⁵⁰. Even though mitochondria are exceptionally dynamic in nature, the contact sites between the mitochondria and ER seem to remain relatively stable, underscoring their physiological significance ⁵¹.

Figure 2. Mitochondrial Fission.

Constriction of the mitochondrial membrane is first initiated by the ER at ER/mitochondria contact sites. After constriction by the ER, the mitochondrial membrane is “marked” for fission, thus resulting in Drp1 recruitment by Drp1 receptors. Drp1 then forms oligomers around the constriction site and further constricts the membrane through GTPase activity, leading to Dyn2/Dnm2 recruitment, additional GTP hydrolysis, and completion of the process of fission resulting in two separate mitochondria.

It has been proposed that the role of the ER is to mark the initial site for mitochondrial constriction and fission ^47,52. Indeed, Korobova et al. demonstrate that the ER-localized inverted formin 2 (INF2) induces actin polymerization between ER and mitochondrial contact sites, which drives initial constriction of mitochondrial fission sites ⁵². This is essential, because Drp1 oligomers are unable to wrap around the mitochondrial membrane and induce fission without initial constriction from another source. Mitochondria have a diameter of ~200 nm or more, depending on the cell type, while Drp1 oligomers sense and bind to mitochondrial membranes with a diameter of ~110–130 nm, before further constricting the membrane ⁴⁷. In line with this, it has been observed that ER-constricted sites have a diameter of ~138–146 nm, suggesting that ER-initiated constriction is an essential prelude to the formation of Drp1 oligomers at mitochondrial membrane constriction sites ⁴⁷.

3.2.2. Drp1

Drp1 is mainly localized to the cytoplasm, meaning that it must be recruited to mitochondria to complete mitochondrial fission. Unlike its family member and related protein, Dyn2/Dnm2, Drp1 does not possess a lipid-binding pleckstrin homology domain, and is unable to bind directly to the mitochondrial membrane ^41,53. Accordingly, mitochondrial resident proteins must act as binding sites or receptors for Drp1 at the constriction sites (Fig. 2). In mammalian cells, many Drp1 receptors on mitochondria have been identified, including mitochondrial fission 1 protein (Fis1), mitochondrial fission factor (Mff), and mitochondrial dynamics protein of 49 kDa and 51 kDa (MiD49/MiD51) ^54–58. Studies have found that Fis1 localizes indiscriminately along the mitochondrial membrane, while Mff and the MiD proteins have a more restricted localization to punctae along the mitochondrial membrane. Although all the Drp1 receptors are able to recruit Drp1 to the outer mitochondrial membrane, evidence suggests that Mff has the more predominant role ⁵⁴. Once recruited to the mitochondrial membrane, Drp1 forms a circular oligomer that uses its GTPase activity to further constrict the mitochondria, but does not complete the fission process due to constriction limits ⁵⁹ (Fig. 2).

3.2.3. Dyn2/Dnm2

Dyn2/Dnm2has been well-established as the major membrane pinching and fission protein at the neck of budding clathrin-coated vesicles at the plasma membrane ⁶⁰. Similar to Drp1, Dyn2/Dnm2molecules form a circular oligomer around the membrane and following GTP hydrolysis, fission is completed ⁶¹. Until recently, it was thought that after the initial mitochondrial constriction generated by the ER, Drp1 would further constrict the mitochondria until a single mitochondria split into two separate membranes, completing a fission event. New evidence now demonstrates that Dyn2/Dnm2 not only acts at the plasma membrane, but also has a vital role in the advanced stages of mitochondrial fission, following initial constriction by the ER and Drp1 ⁴⁰. The crucial role of both GTPase proteins in mitochondrial fission is demonstrated by experiments showing that if either protein is depleted, the mitochondria become elongated and display a more elaborate tubular network ⁴⁰. Such experiments by Lee et al. further highlight the growing appreciation of previously uncharacterized links between endocytic pathways and mitochondria ⁴⁰.

4. Expanding the regulation of Mitochondrial Fusion and Fission

Traditionally, mitochondrial homeostasis was relegated to the regulation of the GTPase proteins, Mfn1/2, OPA1, Drp1, their mitochondrial outer membrane receptors, and more recently, Dyn2/Dnm2. Perhaps surprisingly, only very recently has the vast complexity of mitochondria homeostasis regulation been revealed as far more intricate than previously imagined. Upstream events associated with the trafficking and regulation of the known regulatory proteins are essential for the regulation of the fusion/fission GTPase proteins, thus providing a mechanism for indirectly regulating the rates of mitochondrial fusion and fission. In addition, many of the new indirect mitochondrial regulatory proteins have also been implicated in mitochondrial-related diseases (Table 1).

One key protein that indirectly regulates mitochondrial homeostasis through the trafficking of various mitochondrial proteins is vacuolar protein sorting-35 (VPS35) ^62–64. VPS35 is a subunit of the retromer cargo selective complex (CSC). The retromer CSC is comprised of three main vacuolar protein sorting proteins termed, VPS26, VPS29, and VPS35, and is usually affiliated with one or more sorting nexin proteins ⁶⁵. The original function ascribed to the mammalian retromer complex was to retrieve mannose 6-phosphate receptor from peripheral endosomes to the Golgi complex ⁶⁶. In addition to the mannose 6-phosphate receptor, other identified cargo include the iron transporter DMT1-11/Slc11a2 ⁶⁷, the Wnt transport protein Wntless/MIG-14 ⁶⁸, and others. Exciting new studies implicate VPS35 and the retromer complex in PD and the regulation of mitochondrial fusion and fission, establishing a novel connection between an endocytic trafficking complex and the mitochondrion, a non-endocytic organelle. However, while VPS35 has a definite relationship with mitochondrial dynamics and PD, the mechanism(s) by which VPS35 regulates mitochondrial morphology remains somewhat controversial.

4.1. Indirect Role of VPS35 in Mitochondrial Fusion

Proteins associated with the fusion of mitochondrial membranes may be regulated by post-translational modifications, with one key modification being ubiquitination. The ubiquitination of mitochondrial-membrane-associated Mfn2 targets this fusion protein for proteasomal degradation, thus limiting mitochondrial fusion. A recent study has demonstrated that VPS35 affects this mechanism of Mfn2 regulation, most likely by controlling the trafficking of the E3 ubiquitin ligase, MUL1, to the mitochondrial membrane ⁶⁴. Tang et al. have shown that VPS35-depletion in mouse dopamine neurons induces a PD-like condition, which presents with α-synuclein deposition, fragmented mitochondria and cell death ⁶⁴. In this scenario, VPS35 interacts with MUL1 and sequesters it in the cytoplasm; the release of MUL1 from this interaction is thought to facilitate its transport to the mitochondrial membrane, where it ubiquitinates Mfn2 and induces the latter’s proteasomal degradation ⁶⁴ (Fig. 3). Upon VPS35 dysfunction, MUL1 is more freely available at the mitochondrial membrane, leading to enhanced Mfn2 degradation, fewer fusion events, and thus fragmented mitochondrial morphology.

Fig. 3. Potential roles of VPS35 in mitochondrial fission/fusion.

Model representing the role of VPS35 (pink) in mitochondrial fission (bottom left) or mitochondrial fusion (top right). For fission, VPS35 removes inactive Drp1 (red) and traffics it to the lysosome for degradation, to allow active Drp1 (green) to further constrict the OMM. For fusion, VPS35 regulates MUL1 (orange) localization to the OMM, where it binds to Mfn2 (red) and induces its polyubiquitination (yellow) to target it for proteasomal degradation.

4.2.1. Indirect role of VPS35 in Mitochondrial Fission

While VPS35 may regulate mitochondrial fusion by its control of MUL1, a recent study provides evidence for a different model for VPS35 function in the regulation of mitochondrial fission. Wang et al. demonstrated that VPS35 binds to complexes of Drp1 on the mitochondrial membrane that are considered inactive. By binding to these complexes on the mitochondrial membrane, vesicles containing VPS35 (and perhaps the entire retromer CSC) are proposed to promote the generation of mitochondrial-derived vesicles (MDVs) and remove the inactive Drp1 for transport to lysosomes for degradation ^62,63 (Fig. 3). Subsequently, this frees up constriction sites for the recruitment and/or activation of Drp1 and promotes mitochondrial fission and fragmentation ^62,63. MDVs are defined as structures with diameters of 70–150 nm ⁶⁹, and are considered quality control mechanisms for mitochondria that deliver mitochondria-related contents to the late endosome or multivesicular bodies ⁷⁰. Although the exact mechanism of incorporation of the selected cargo is unclear, studies have shown that both the outer and inner membranes can be used to form MDVs, carrying membrane bound or mitochondrial matrix proteins ^70–74. It is noteworthy that a mutated form of VPS35 commonly found in PD, VPS35^D620N, causes extensive mitochondrial fragmentation and loss of function, providing additional insight to the mechanism by which VPS35 affects PD.

4.2.2. Indirect Role of Retromer-Associated Proteins: EHD1 and Rabankyrin-5

Given the crucial role of VPS35 in mitochondrial homeostasis and related diseases, it would not be surprising to find that retromer CSC, accessory proteins, or interaction partners might also influence mitochondrial fusion and fission. For example, several VPS26A mutations have been implicated in atypical PD ^75,76. Moreover, a recent study has demonstrated that extended/accessory members of the retromer complex, including the Eps15 homology domain protein 1 (EHD1), and its interaction partner, Rabankyrin-5, also influence mitochondrial homeostasis ⁷⁷. EHD1, an ATPase with homology to the dynamin family of GTPases, has a well-established role in regulating recycling from the endocytic recycling compartment to the plasma membrane, and likely functions in the fission of tubules and vesicles from endosomes ^78–80. Recent studies have demonstrated a link between EHD1 and the retromer ⁸¹, although apparently independent of Rabankyrin-5 ^81,82, suggesting that EHD1 and Rabankyrin-5 somehow function upstream of the mitochondrial fission and fusion proteins.

As predicted, both EHD1 and Rabankyrin-5 affect mitochondrial homeostasis and dynamics ⁷⁷. Upon either EHD1- or Rabankyrin-5-depletion, mitochondria become highly static and elongated in nature, reminiscent of Drp1-depletion. Although an interaction was observed between EHD1 and MUL1, the ubiquitin ligase responsible for regulating Mfn2, the latter’s expression levels failed to increase as anticipated if less proteasomal degradation of Mfn2 was occurring upon EHD1-depletion ⁷⁷. Accordingly, EHD1 and Rabankyrin-5 most likely regulate VPS35 expression and/or its subcellular distribution, potentially controlling the level of active Drp1 at mitochondrial constriction sites.

The regulation of both retromer and mitochondrial homeostasis by EHD1 and Rabankyrin-5, both interactors and/or effectors of small Rab GTP-binding proteins, suggests that the Rab-family of proteins may also bear impact on mitochondrial function. Although links between Rab proteins and mitochondrial homeostasis remain elusive, a large body of literature does support the involvement of many different Rab GTP-binding proteins in PD (reviewed in ⁸³). At least one Rab protein, Rab32, localizes to the mitochondrial membrane and interacts with the PD-related protein, Leucine-rich repeat kinase 2 (LRRK2) ⁸⁴. Strikingly, Rab7, which also functionally interacts with LRRK2 ⁸⁵ has also been implicated in recruitment of the retromer CSC to the endosomal membrane ⁸⁶. Thus, it would be tempting to speculate that Rab7 might influence PD not only through its relationship with LRRK2, but also by its regulation of the retromer, and subsequently, mitochondrial homeostasis.

5. Future Perspectives

Growing recognition of the relationships between endocytic regulatory proteins and mitochondria has shed light on novel mechanisms involved in mitochondrial homeostasis. In addition to the bifunctional role for the GTPase Dyn2/Dnm2 in both endocytic fission at the plasma membrane and in mitochondrial fission, the involvement of the retromer and its interaction proteins in mitochondrial homeostasis has further solidified the links between endocytic pathways and mitochondria. It remains to be determined whether additional endocytic regulatory complexes that function in coordination with the retromer, including the WASH complex ⁸⁷, the newly-discovered retriever complex ⁸⁸, and the Command (CCC) complex ⁸⁹ might also influence mitochondrial homeostasis. Moreover, whether mitochondrial fusion and fission proteins play any role in endocytic regulation remains entirely unknown.

SYNOPSIS.

The mitochondrion is the major energy producing cellular organelle. There is a growing appreciation that mitochondrial function is regulated by the dynamics of its membrane fusion and fission. Herein, we review the known GTPases involved in mitochondrial fusion and fission, and highlight recent studies addressing their mechanisms of regulation. In particular, we review the involvement of the retromer complex in mitochondrial homeostasis, and we speculate that cross-regulation between endocytic and mitochondrial pathways may be more widespread than previously assumed.