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Mitochondrial fusion but not fission regulates larval growth and synaptic development through steroid hormone production.

Sandoval H, Yao CK, Chen K, Jaiswal M, Donti T, Lin YQ, Bayat V, Xiong B, Zhang K, David G, Charng WL, Yamamoto S, Duraine L, Graham BH, Bellen HJ - Elife (2014)

Bottom Line: Marf is required to form contacts between the endoplasmic reticulum and/or lipid droplets (LDs) and for proper storage of cholesterol and ecdysone synthesis in ring glands.Interestingly, human Mitofusin-2 rescues the loss of LD but both Mitofusin-1 and Mitofusin-2 are required for steroid-hormone synthesis.Our data show that Marf and Mitofusins share an evolutionarily conserved role in mitochondrial transport, cholesterol ester storage and steroid-hormone synthesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.

ABSTRACT
Mitochondrial fusion and fission affect the distribution and quality control of mitochondria. We show that Marf (Mitochondrial associated regulatory factor), is required for mitochondrial fusion and transport in long axons. Moreover, loss of Marf leads to a severe depletion of mitochondria in neuromuscular junctions (NMJs). Marf mutants also fail to maintain proper synaptic transmission at NMJs upon repetitive stimulation, similar to Drp1 fission mutants. However, unlike Drp1, loss of Marf leads to NMJ morphology defects and extended larval lifespan. Marf is required to form contacts between the endoplasmic reticulum and/or lipid droplets (LDs) and for proper storage of cholesterol and ecdysone synthesis in ring glands. Interestingly, human Mitofusin-2 rescues the loss of LD but both Mitofusin-1 and Mitofusin-2 are required for steroid-hormone synthesis. Our data show that Marf and Mitofusins share an evolutionarily conserved role in mitochondrial transport, cholesterol ester storage and steroid-hormone synthesis.

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Related in: MedlinePlus

Mitochondrial trafficking defect in Marf mutants cannot be rescued by motor neuron expression of human MFN1 or MFN2.Mutations and controls were crossed to a motor neuron (MN) driver (D42-GAL4, UAS-mitoGFP) to label neuronal mitochondria. (A) Ventral nerve cord (VNC), MN-knockdown of dmiro in Marf mutant exhibit more clustered mitochondria in the soma compared to Marf alone, while neither MN-expression of MFN1 or MFN2 rescued the VNC mitochondrial trafficking defect of Marf mutants. (B) At the proximal end of the A3 axon, MN-knockdown of dmiro in Marf mutants had severed reduction of mitochondrial trafficking compared to Marf alone. (C) Neither MN-expression of MFN1 or MFN2 rescued the mitochondrial trafficking defect of Marf mutants in boutons co-stained with post-synaptic marker Discs Large 1 (Dlg1).DOI:http://dx.doi.org/10.7554/eLife.03558.010
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fig3s2: Mitochondrial trafficking defect in Marf mutants cannot be rescued by motor neuron expression of human MFN1 or MFN2.Mutations and controls were crossed to a motor neuron (MN) driver (D42-GAL4, UAS-mitoGFP) to label neuronal mitochondria. (A) Ventral nerve cord (VNC), MN-knockdown of dmiro in Marf mutant exhibit more clustered mitochondria in the soma compared to Marf alone, while neither MN-expression of MFN1 or MFN2 rescued the VNC mitochondrial trafficking defect of Marf mutants. (B) At the proximal end of the A3 axon, MN-knockdown of dmiro in Marf mutants had severed reduction of mitochondrial trafficking compared to Marf alone. (C) Neither MN-expression of MFN1 or MFN2 rescued the mitochondrial trafficking defect of Marf mutants in boutons co-stained with post-synaptic marker Discs Large 1 (Dlg1).DOI:http://dx.doi.org/10.7554/eLife.03558.010

Mentions: Recently, mammalian MFN2 was shown to physically interact with MIRO2, an adaptor protein for motor proteins required for mitochondrial trafficking (Misko et al., 2010). Drosophila miro (dmiro) mutants are severely impaired in mitochondrial trafficking in the VNC (Guo et al., 2005). Indeed, RNAi knockdown of dmiro almost abolishes the presence of mitochondria in axons, a phenotype that is much more severe than what we observe in Marf mutants (data not shown). Moreover, loss of dmiro in Marf mutant MNs largely enhances the mitochondrial trafficking defect in the VNC and proximal axons (Figure 3—figure supplement 2A,B). This suggests that Marf cannot be the sole anchor that binds dMiro for mitochondrial trafficking.


Mitochondrial fusion but not fission regulates larval growth and synaptic development through steroid hormone production.

Sandoval H, Yao CK, Chen K, Jaiswal M, Donti T, Lin YQ, Bayat V, Xiong B, Zhang K, David G, Charng WL, Yamamoto S, Duraine L, Graham BH, Bellen HJ - Elife (2014)

Mitochondrial trafficking defect in Marf mutants cannot be rescued by motor neuron expression of human MFN1 or MFN2.Mutations and controls were crossed to a motor neuron (MN) driver (D42-GAL4, UAS-mitoGFP) to label neuronal mitochondria. (A) Ventral nerve cord (VNC), MN-knockdown of dmiro in Marf mutant exhibit more clustered mitochondria in the soma compared to Marf alone, while neither MN-expression of MFN1 or MFN2 rescued the VNC mitochondrial trafficking defect of Marf mutants. (B) At the proximal end of the A3 axon, MN-knockdown of dmiro in Marf mutants had severed reduction of mitochondrial trafficking compared to Marf alone. (C) Neither MN-expression of MFN1 or MFN2 rescued the mitochondrial trafficking defect of Marf mutants in boutons co-stained with post-synaptic marker Discs Large 1 (Dlg1).DOI:http://dx.doi.org/10.7554/eLife.03558.010
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215535&req=5

fig3s2: Mitochondrial trafficking defect in Marf mutants cannot be rescued by motor neuron expression of human MFN1 or MFN2.Mutations and controls were crossed to a motor neuron (MN) driver (D42-GAL4, UAS-mitoGFP) to label neuronal mitochondria. (A) Ventral nerve cord (VNC), MN-knockdown of dmiro in Marf mutant exhibit more clustered mitochondria in the soma compared to Marf alone, while neither MN-expression of MFN1 or MFN2 rescued the VNC mitochondrial trafficking defect of Marf mutants. (B) At the proximal end of the A3 axon, MN-knockdown of dmiro in Marf mutants had severed reduction of mitochondrial trafficking compared to Marf alone. (C) Neither MN-expression of MFN1 or MFN2 rescued the mitochondrial trafficking defect of Marf mutants in boutons co-stained with post-synaptic marker Discs Large 1 (Dlg1).DOI:http://dx.doi.org/10.7554/eLife.03558.010
Mentions: Recently, mammalian MFN2 was shown to physically interact with MIRO2, an adaptor protein for motor proteins required for mitochondrial trafficking (Misko et al., 2010). Drosophila miro (dmiro) mutants are severely impaired in mitochondrial trafficking in the VNC (Guo et al., 2005). Indeed, RNAi knockdown of dmiro almost abolishes the presence of mitochondria in axons, a phenotype that is much more severe than what we observe in Marf mutants (data not shown). Moreover, loss of dmiro in Marf mutant MNs largely enhances the mitochondrial trafficking defect in the VNC and proximal axons (Figure 3—figure supplement 2A,B). This suggests that Marf cannot be the sole anchor that binds dMiro for mitochondrial trafficking.

Bottom Line: Marf is required to form contacts between the endoplasmic reticulum and/or lipid droplets (LDs) and for proper storage of cholesterol and ecdysone synthesis in ring glands.Interestingly, human Mitofusin-2 rescues the loss of LD but both Mitofusin-1 and Mitofusin-2 are required for steroid-hormone synthesis.Our data show that Marf and Mitofusins share an evolutionarily conserved role in mitochondrial transport, cholesterol ester storage and steroid-hormone synthesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.

ABSTRACT
Mitochondrial fusion and fission affect the distribution and quality control of mitochondria. We show that Marf (Mitochondrial associated regulatory factor), is required for mitochondrial fusion and transport in long axons. Moreover, loss of Marf leads to a severe depletion of mitochondria in neuromuscular junctions (NMJs). Marf mutants also fail to maintain proper synaptic transmission at NMJs upon repetitive stimulation, similar to Drp1 fission mutants. However, unlike Drp1, loss of Marf leads to NMJ morphology defects and extended larval lifespan. Marf is required to form contacts between the endoplasmic reticulum and/or lipid droplets (LDs) and for proper storage of cholesterol and ecdysone synthesis in ring glands. Interestingly, human Mitofusin-2 rescues the loss of LD but both Mitofusin-1 and Mitofusin-2 are required for steroid-hormone synthesis. Our data show that Marf and Mitofusins share an evolutionarily conserved role in mitochondrial transport, cholesterol ester storage and steroid-hormone synthesis.

Show MeSH
Related in: MedlinePlus