Mitofusin-2 is a protein that in humans is encoded by the ''MFN2'' gene. Mitofusins are

GTPase GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a ...

s embedded in the outer membrane of the mitochondria. In mammals

MFN1 Mitofusin-1 is a protein that in humans is encoded by the ''MFN1'' gene. The protein encoded by this gene is a mediator of mitochondrial fusion. This protein and mitofusin 2 are homologs of the ''Drosophila ''Drosophila'' () is a genus of fl ...

and MFN2 are essential for

mitochondrial fusion Mitochondria are dynamic organelles with the ability to fuse and divide ( fission), forming constantly changing tubular networks in most eukaryotic cells. These mitochondrial dynamics, first observed over a hundred years ago are important for the ...

. In addition to the mitofusins,

OPA1 Dynamin-like 120 kDa protein, mitochondrial is a protein that in humans is encoded by the ''OPA1'' gene. This protein regulates mitochondrial fusion and cristae structure in the inner mitochondrial membrane (IMM) and contributes to ATP synthesis a ...

regulates inner mitochondrial membrane fusion, and

DRP1 Dynamin-1-like protein is a GTPase that regulates mitochondrial fission. In humans, dynamin-1-like protein, which is typically referred to as dynamin-related protein 1 (Drp1), is encoded by the ''DNM1L'' gene and is part of the dynamin superfamily ...

is responsible for mitochondrial fission. Mitofusin-2 (MFN2) is a mitochondrial membrane protein that plays a central role in regulating

and cell metabolism. More specifically, MFN2 is a dynamin-like

embedded in the outer mitochondrial membrane (OMM) which in turn affects mitochondrial dynamics, distribution, quality control, and function. In addition to the MFN2,

regulates inner mitochondrial membrane fusion,

is a mediator of mitochondrial fusion and

is responsible for mitochondrial fission.

Structure

The human mitofusin-2 protein contains 757

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

residues. The MFN2 comprises a large cytosolic GTPase domain at the N-terminal, followed by a coiled-coil heptad-repeat (HR1) domain, a proline-rich (PR) region, two sequential transmembrane (TM) domains crossing the OMM and a second cytosolic heptad-repeat (HR2) domain at the C-terminal. MFN2 has been shown by

electron microscopy An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...

(EM) to accumulate in contact regions between adjacent mitochondria, supporting their role in mitochondrial fusion. Seminal studies revealed that both, MFN1 and MFN2 spanning from the OMM of two opposing mitochondria, physically interact in trans, by the formation of antiparallel dimers between their HR2 domains.

Function

A pivotal in vivo study revealed that MFN2 is essential for embryonic development, thus, the deletion of MFN2 in mice is lethal during midgestation. The inactivation of ''MFN2'' alleles after placentation also revealed that MFN2 ablation severely impairs cerebellum development. It has been also described that Mfn1 and Mfn2 are ubiquitously expressed yet they display different relative levels of expression between tissues, with MFN2 being the predominantly expressed mitofusin in the brain and MFN1 in the heart. This tissue-specific expression could be one of the reasons its ablation induces cerebellar-specific impairments. CC-BY icon

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Mitochondrial fusion and fission

MFN2 is a mitochondrial membrane protein that participates in

and contributes to the maintenance and operation of the mitochondrial network. Mitochondria function as a dynamic network constantly undergoing

fusion Fusion, or synthesis, is the process of combining two or more distinct entities into a new whole. Fusion may also refer to: Science and technology Physics *Nuclear fusion, multiple atomic nuclei combining to form one or more different atomic nucl ...

and fission. The balance between fusion and fission is important in maintaining the integrity of the mitochondria and facilitates the mixing of the membranes and the exchange of DNA between mitochondria. MFN1 and MFN2 mediate outer membrane fusion,

is involved in inner membrane fusion, and

is responsible for mitochondrial fission. Mitochondrial fusion is unique because it involves two membranes: the OMM and the inner mitochondrial membrane (IMM), that must be rearranged in a coordinated manner in order to maintain

organelle In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' the ...

integrity. Recent studies have shown that MFN2-deficient cells display an aberrant mitochondrial morphology, with a clear fragmentation of the network. Mitochondrial fusion is essential for embryonic development. Knockout mice for either MFN1 or MFN2 have fusion deficits and die midgestation. MFN2 knockout mice die at embryonic day 11.5 due to a defect in the giant cell layer of the placenta. Mitochondrial fusion is also important for mitochondrial transport and localization in neuronal processes. Conditional MFN2 knockout mice show degeneration in the Purkinje cells of the cerebellum, as well as improperly localized mitochondria in the dendrites. MFN2 also associates with the MIRO-Milton complex which links the mitochondria to the kinesin motor.

ER-mitochondria contacts

MFN2 has also been suggested to be a key regulator of ER-mitochondria contiguity, though its exact function in this inter-organelle still remains unknown. Small fractions of MFN2 have been observed to be located in ER membranes, particularly in the so called ER mitochondria-associated membranes (MAM). Several processes known to take place at MAM, such as autophagosomes formation have been claimed to be modulated by the presence of MFN2.

Axonal transport of mitochondria

MFN2 has been proposed to be essential for the transport of mitochondria along axons, being involved in their attachment to microtubules through interaction with the two main motor proteins Miro and Milton. Other intracellular pathways, such as cell cycle progression, maintenance of mitochondrial bioenergetics, apoptosis, and autophagy, have been demonstrated to be modulated by MFN2.

Clinical significance

The importance of a regulated mitochondrial morphology in cell physiology makes immediately clear the potential impact of MFN2 in the onset/progression of different pathological conditions.

Charcot–Marie–Tooth disease type 2A (CMT2A)

Charcot-Marie-Tooth disease type 2A (CMT2A) is caused by mutations in the ''MFN2'' gene. ''MFN2'' mutations are linked to neurological disorders characterized by a wide clinical phenotype that involves the central and peripheral nervous system. The impairment of the former is rarer while

neuropathy Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...

forms are more frequent and severe, involving both legs and arms, with weakness, sensory loss, and optical atrophy. All these complex phenotypes are clinically collected in the neurological disorder CMT2A, a subtype of a heterogeneous group of congenital neuromuscular diseases which affect motor and sensory neurons, called CMT disease. Among different cell types, neurons are particularly sensitive to MFN2 defects: to work properly, these cells need functional mitochondria located at specific sites to support adequate ATP production and Ca²⁺ buffering. A defective mitochondrial fusion has been suggested to participate in the pathogenesis of CMT2A. Another important cell feature altered in the presence of MFN2 mutations is mitochondrial transport and indeed current models propose this defect as the major cause of CMT2A. Mutations in OPA1 also cause optic atrophy, which suggests a common role of

in neuronal dysfunction. The exact mechanism of how mutations in MFN2 selectively cause the degeneration of long peripheral axons is not known. There is evidence suggesting that it could be due to defects in the

axonal transport Axonal transport, also called axoplasmic transport or axoplasmic flow, is a cellular process responsible for movement of mitochondria, lipids, synaptic vesicles, proteins, and other organelles to and from a neuron's cell body, through the cytoplas ...

of mitochondria.

Alzheimer's disease

Increasing evidence suggests a possible link between MFN2 deregulation and

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...

(AD). In particular, MFN2 protein and mRNA levels are decreased in the frontal cortex of patients with AD, as well as in hippocampal neurons of post-mortem AD patients. Notably, the cortex and hippocampus are the brain's areas in which a major neuronal impairment is observed in AD. Interestingly, the ''MFN2'' gene is located on chromosome 1p36, which has been suggested to be an AD-associated locus. However, it is currently unknown whether MFN2 alterations are causative for the pathology or just a consequence of AD. In particular, it is not clear if MFN2 is linked to AD through its effects on mitochondria or by affecting other pathways. In summary, mitochondrial dysfunction is a prominent feature of AD

neurons A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

. It has been described that levels of DRP1 ,

, and MFN2 are significantly reduced whereas levels of

Fis1 Mitochondrial fission 1 protein (FIS1) is a protein that in humans is encoded by the ''FIS1'' gene on chromosome 7. This protein is a component of a mitochondrial complex, the ARCosome, that promotes mitochondrial fission. Its role in mitochond ...

are significantly increased in AD.

Parkinson's disease

MFN2 is a key substrate of the

PINK1 PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase encoded by the ''PINK1'' gene. It is thought to protect cells from stress-induced mitochondrial dysfunction. PINK1 activity causes the parkin protein to bind to d ...

/parkin couple, whose mutations are linked to the familial forms of Parkinson's disease (PD). MFN2 has been demonstrated to be essential for axonal projections of midbrain dopaminergic (DA)

that are affected in PD. MFN2 alterations in the progression of PD, considering the capacity of PINK1 and parkin to trigger post-translational modifications in their substrates, have yet to be evaluated.

Obesity/diabetes/insulin resistance

The MFN2 protein may play a role in the pathophysiology of obesity. In obesity and type II diabetes, MFN2 expression has been found to be reduced. In turn, MFN2 down-regulation activates JNK pathway, favouring the formation of lipid intermediates that lead to insulin resistance. Recent studies have also shown that mitochondria arrest fusion by down-regulating MFN2 in obesity and diabetes, which leads to a fragmented mitochondrial network. This fragmentation is obvious in the pancreatic beta-cells in the Islets of Langerhans and can inhibit mitochondrial quality control mechanisms such as

mitophagy Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described over a hundred years ago by Margaret Reed Lewis and Warren Harmo ...

and

autophagy Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent r ...

- leading to a defect in insulin secretion and eventual beta-cell failure. The expression of MFN2 in skeletal muscle is proportional to insulin sensitivity in this tissue, and its expression is reduced in high-fat diet fed mice and Zucker fatty rats.

Cardiomyopathies

In heart, the embryonic combined MFN1/MFN2 deletion is lethal for mice embryo, while in adults it induces a progressive and lethal dilated

cardiomyopathy Cardiomyopathy is a group of diseases that affect the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...

. A modest

cardiac hypertrophy Ventricular hypertrophy (VH) is thickening of the walls of a ventricle (lower chamber) of the heart. Although left ventricular hypertrophy (LVH) is more common, right ventricular hypertrophy (RVH), as well as concurrent hypertrophy of both ventr ...

, associated to a tendency of MFN2-deprived mitochondria was observed caused by an increased resistance to Ca²⁺-mediated cell death stimuli. While it is undisputed the importance of MFN2 in

cardiomyocytes Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle tha ...

physiology, clarification of whether its pro-fusion activity or other functionalities of the protein are involved will require further investigations.

Cancer

Studying the mechanisms of mitochondrial function, more specifically MFN2 function, during tumorigenesis is critical for the next generation of cancer therapeutics. Recent studies have shown that dysregulation of the mitochondrial network can have an effect on MFN2 proteins, provoking mitochondrial hyperfusion and a multidrug resistant (MDR) phenotype in cancer cells. MDR cancer cells have a much more aggressive behaviour and they are very invasive with a better ability to metastasize. All these factors lead to a poor cancer prognosis and, therefore, novel therapeutic strategies for targeting and eradicating MDR TNBC cells are required. It has been hypothesized that mitochondrial hyperfusion is one of the main mechanisms that makes cells resistant to traditional chemotherapy treatments. Hence, inhibiting mitochondrial fusion would sensitize cancer cells to chemotherapy, making it a significantly more effective treatment. In order to inhibit mitochondrial hyperfusion, an anti-MFN2 peptide has to be used, in order to bind to the mitochondria membrane MFN2 proteins to prevent them from building the mitochondrial network. The aim of the anti-MFN2 peptide is to make MFN2 not functional so it cannot participate in mitochondrial fusion and in the operation of the mitochondrial network. In this way, hyperfusion will not occur and chemotherapy drugs would be much more successful. However, further investigations are required in this field as there are still lots of unknowns.

References

External links

GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 2
* {{PDBe-KB2, O95140, Mitofusin-2