Mitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons

Lee, Seungmin; Sterky, Fredrik; Mourier, Arnaud; Terzioglu, Mügen; Cullheim, Staffan; Olson, Lar̀s; Larsson, Nils‐Göran

doi:10.1093/hmg/dds352

Cited by 143 publications

(130 citation statements)

References 38 publications

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“…Parkin-mediated ubiquitination of outer mitochondrial membrane proteins targets the mitochondria for engulfment by the autophagosome. In support of this model, loss of MFN2 prevents Parkin from docking to depolarized mitochondria (78,79). Therefore, inhibition of Parkin-MFN2 docking or MFN2 phosphorylation will block mitophagy.…”

Section: Control Of Cardiac Mitochondrial Biogenesis and Dynamics: Thmentioning

confidence: 69%

Cardiac nuclear receptors: architects of mitochondrial structure and function

Vega¹,

Kelly²

2017

Journal of Clinical Investigation

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The adult mammalian heart has immense energy demands in order to support its role as a constantly active pump. Indeed, the human heart generates and utilizes kilogram quantities of ATP each day. The vast majority of ATP produced in the cardiac myocyte is generated via oxidative phosphorylation (OXPHOS) within a very-high-capacity mitochondrial system. The heart must continually adapt to changing physiologic conditions that influence workload, as well as alterations in oxygen and energy substrate availability. Notably, given that the heart has a limited capacity for fuel storage, it must utilize several energy substrates in an efficient and dynamic manner. As will be described, members of the nuclear receptor transcription factor superfamily serve to dynamically control preference and capacity for cardiac mitochondrial fuel metabolism during development and in response to myriad physiologic conditions. In addition, alterations in nuclear receptor signaling occur with pathologic cardiac growth and remodeling en route to heart failure.The adult cardiac myocyte has a higher density of mitochondria than any other cell type (1). The biogenesis of this highcapacity mitochondrial system occurs largely during the perinatal stage of development. This process involves a major burst of mitochondrial biogenesis at birth, followed by a period of mitochondrial maturation and remodeling during the postnatal period (2). Recent evidence indicates that postnatal mitochondrial maturation involves highly coordinated events including mitophagy, biogenesis, and dynamics (fusion and fission), resulting in a mitochondria network that is densely packed between sarcomeres to directly supply ATP to support cardiac contraction (2). The adult cardiac mitochondria are equipped with enzymatic machinery capable of oxidizing multiple substrates including fatty acids (the chief fuel) as well as glucose (pyruvate) and ketone bodies. This mitochondrial developmental maturation process occurs in parallel with well-characterized changes in the expression of contractile apparatus isoforms, ion channels, and calcium handling proteins. The collective perinatal programming in energy metabolic and structural genes results in an efficient and enduring pump for the adult life of the organism.The postnatal heart has an amazing capacity to oxidize multiple fuels and, therefore, is "omnivorous." Pioneering work by multiple groups has defined dynamic shifts in fuel utilization capacity and preferences during development and in disease states. The fetal and immediate postnatal heart relies primarily on glucose (glycolysis) and lactate as energy sources (3-5). However, very soon after birth the heart shifts to fatty acids as the major fuel substrate, coincident with the mitochondrial biogenic response (Figure 1 and refs. 5-8). The level of glucose oxidation also increases (8). The postnatal heart is also capable of oxidizing ketones, albeit at a low level, concomitant with the postnatal rise in circulating ketones (5). The shifts in fuel preference after birth ar...

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Section: Control Of Cardiac Mitochondrial Biogenesis and Dynamics: Thmentioning

confidence: 69%

Cardiac nuclear receptors: architects of mitochondrial structure and function

Vega¹,

Kelly²

2017

Journal of Clinical Investigation

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“…Nevertheless, the seemingly paradoxical finding of mitochondrial enlargement after tissue-specific Mfn2 ablation is also observed in hepatocytes 80 and neurons. 81 Collectively, these studies support an essential role for Mfn2 in culling abnormal mitochondria, independent of its effects in promoting mitochondrial fusion. To discover the mechanistic basis for impaired mitophagy in the absence of Mfn2, we examined the consequences of Mfn2 (and Mfn1) cardiac ablation on PINK1-Parkin pathway activity, 82 We observed that Parkin and Mfn2 co-immunoprecipitate in HEK293 cells and adult myocardium, and determined that their physical association depends upon PINK1-mediated phosphorylation of Mfn2 on T111 and S442.…”

Section: Mfn2 As An Orchestrator Of Mitochondrial Fatementioning

confidence: 83%

Mitochondrial Dynamism and Cardiac Fate

Dorn¹

2013

Circ J

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Defects in mitochondrial biogenesis are well known to contribute to cardiac dysfunction. By contrast, mechanistic details of essential homeostatic mechanisms that maintain mitochondrial health in the heart are only recently being uncovered, and the pathological potential of these processes is largely hypothetical. I will review the role of mitochondrial dynamics, focusing on cyclic organelle fission and fusion, in normal and diseased hearts. Special attention is given to recent insights into the non-canonical functioning of the mitofusin 2 (Mfn2) outer mitochondrial membrane fusion protein as a regulator of sarcoplasmic-reticular calcium crosstalk and a critical determinant of mitophagic culling of damaged mitochondria. Because mitochondrial fusion in normal adult cardiomyocytes occurs so slowly and infrequently, I postulate that the major function of Mfn2 in the heart may not be to redundantly promote mitochondrial fusion with Mfn1, but to centrally orchestrate mitochondrial quality control. (Circ J 2013; 77: 1370 -1379

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“…26,31,33), and the current observation that mtDNA levels plummet in Mfn2-deficient cardiomyopathic hearts, we have re-evaluated our concept of a mitochondrial life cycle. As the descendents of primordial bacteria that developed endosymbiotic relationships with ancestral unicellular organisms, we believe that mitochondria have no life cycle per se; like the bacteria from which they descended, mitochondria are immortal.…”

Section: Discussionmentioning

confidence: 99%

“…Mfn2 is the essential mitochondrial receptor for Parkin on depolarized mitochondria (9,26). Thus, Mfn2 deficiency produced by cardiac-specific gene ablation interrupts a protective mitophagy pathway, and the resulting accumulation of abnormal mitochondria impairs cardiomyocyte respiration and induces a progressive cardiomyopathy by 16 weeks of age (9).…”

Section: Mtdna Defects In Mfn2-deficient Heartsmentioning

confidence: 99%

“…Nevertheless, cardiomyocyte Mfn2 deletion (but not Mfn1 deletion) provoked development of unusually large dysmorphic mitochondria, cardiomyocyte respiratory dysfunction, and progressive cardiomyopathy (9). The mechanistic basis by which Mfn2 (but not Mfn1) deficiency evokes accumulation of abnormal mitochondria was revealed through its selective ablation in mouse livers, hearts, and neurons (9,26,31,33). Together, these studies describe a central role for Mfn2 in mitochondrial quality control as the essential transduction factor mediating signaling from the mitochondrial PTENinduced putative kinase 1 (PINK1) to the cytosolic E3 ubiquitin ligase Parkin.…”

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confidence: 99%

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Mitochondrial Genome Linearization Is a Causative Factor for Cardiomyopathy in Mice and Drosophila

Chen

Sparks

Bhandari

et al. 2014

Antioxidants & Redox Signaling

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Aims: Mitofusin (Mfn)2 redundantly promotes mitochondrial outer membrane tethering and organelle fusion with Mfn1, and uniquely functions as the mitochondrial receptor for Parkin during PTEN-induced putative kinase 1 (PINK1)-Parkin-mediated mitophagy. Selective deletion of Mfn2 with retention of Mfn1 preserves mitochondrial fusion while rendering damaged mitochondria resistant to normal quality control culling mechanisms. Consequently, neuron and cardiomyocyte-specific Mfn2 gene ablation is associated with accumulation of damaged mitochondria and organ dysfunction. Here, we determined how mitochondrial DNA (mtDNA) damage contributes to cardiomyopathy in Mfn2-deficient hearts. Results: RNA sequencing of Mfn2-deficient hearts revealed increased expression of some nuclear-encoded mitochondrial genes, but mitochondrial-encoded transcripts were not upregulated in parallel and mtDNA content was decreased. Ultra-deep sequencing of mtDNA showed no increase in single nucleotide mutations, but copy number variations representing insertion-deletion (in-del) mutations were induced over time by cardiomyocyte-specific Mfn2 deficiency. Double-strand mtDNA breaks in the form of in-dels were confirmed by polymerase chain reaction, and in the form of linear mitochondrial genomes were identified by southern blot analysis. Linearization of Drosophila cardiomyocyte mtDNA using conditional cardiomyocyte-specific expression of mitochondrial targeted XhoI recapitulated the cardiomyopathy of Mfn2-deficient mouse hearts. Innovation: This is the first description of mitochondrial genome linearization as a causative factor in cardiomyopathy. Conclusion: One of the consequences of interrupting mitochondrial culling by the PINK1-Mfn2-Parkin mechanism is an increase in mtDNA double-stranded breaks, which adversely impact mitochondrial function and DNA replication.

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Mitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons

Cited by 143 publications

References 38 publications

Cardiac nuclear receptors: architects of mitochondrial structure and function

Cardiac nuclear receptors: architects of mitochondrial structure and function

Mitochondrial Dynamism and Cardiac Fate

Mitochondrial Genome Linearization Is a Causative Factor for Cardiomyopathy in Mice and Drosophila

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