1. Mitochondrial fusion but not fission regulates larval growth and synaptic development through steroid hormone production
- Author
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Yong Qi Lin, Chi-Kuang Yao, Vafa Bayat, Taraka R. Donti, Wu Lin Charng, Gabriela David, Bo Xiong, Shinya Yamamoto, Ke Zhang, Hector Sandoval, Lita Duraine, Manish Jaiswal, Hugo J. Bellen, Brett H. Graham, and Kuchuan Chen
- Subjects
rho GTP-Binding Proteins ,lipid droplets ,MFN2 ,lipid droplet ,Mitochondrion ,Endoplasmic Reticulum ,Opa1 ,Mitochondrial Dynamics ,Mitochondrial Membrane Transport Proteins ,Synaptic Transmission ,GTP Phosphohydrolases ,Animals, Genetically Modified ,0302 clinical medicine ,Lipid droplet ,Drosophila Proteins ,MFN1 ,Biology (General) ,Genetics ,0303 health sciences ,General Neuroscience ,Gene Expression Regulation, Developmental ,General Medicine ,Mitochondria ,Cell biology ,Drosophila melanogaster ,Cholesterol ,mitochondrial fusion ,Larva ,Medicine ,Mfn1 and Mfn2 ,Research Article ,Charcot-Marie-Tooth type 2A ,Ecdysone ,QH301-705.5 ,Science ,Longevity ,Neuromuscular Junction ,Drp1 ,Biology ,mitochondria transport ,General Biochemistry, Genetics and Molecular Biology ,Mitochondrial Proteins ,03 medical and health sciences ,Mitochondrial membrane transport protein ,GTP-Binding Proteins ,Animals ,Humans ,Mitochondrial transport ,030304 developmental biology ,General Immunology and Microbiology ,Endoplasmic reticulum ,Genetic Complementation Test ,Membrane Proteins ,Axons ,Cytoskeletal Proteins ,Developmental Biology and Stem Cells ,Mfn1 ,Synapses ,biology.protein ,030217 neurology & neurosurgery ,Neuroscience - 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. DOI: http://dx.doi.org/10.7554/eLife.03558.001, eLife digest Mitochondria are the main source of energy for cells. These vital and highly dynamic organelles continually change shape by fusing with each other and splitting apart to create new mitochondria, repairing and replacing those damaged by cell stress. For nerve impulses to be transmitted across the gaps (called synapses) between nerve cells, mitochondria need to supply the very ends of the nerve fibers with energy. To do this, the mitochondria must be transported from the main body of the nerve cell to the tips of the nerve fibers. This may not happen if mitochondria are the wrong shape, size or damaged. While searching for genetic mutations that disrupt nerve function in the fruit fly Drosophila, Sandoval et al. spotted mutations in a gene called Marf. Further investigations revealed that flies with mutant versions of Marf have small, round mitochondria, and their nerves cannot transmit signals to muscles when they are highly stimulated. This is because the mutant mitochondria are not easily transported along nerve fibers, and so not enough energy is supplied to the synapses. The synapses of the Marf mutants are also abnormally shaped. Sandoval et al. found that this is not because Marf is lost in the neurons themselves, but because it is lost from a hormone-producing tissue called the ring gland. Another problem found in flies with mutated Marf genes is that they stop developing while in their larval stage. Sandoval et al. established that this could also be related to the loss of Marf from the ring gland. The Marf protein has two different functions in the ring gland: forming and storing droplets of fatty molecules used in hormone production, and synthesising a hormone that controls when a fly larva matures into the adult fly. This suggests that the lower levels of this hormone produced by Marf mutant flies underlies their prolonged larval stages and synapse defects. Vertebrates (animals with backbones, such as humans) have two genes that are related to the fly's Marf gene. When the human forms of these genes were introduced into mutant flies that lack a working copy of Marf, hormone production was only restored if both genes were introduced together. This indicates that these genes have separate roles in vertebrates, but that these roles are both performed by the single fly gene. The role of Marf in tethering mitochondria in the ring gland may allow us to better understand how this process affects hormone production and how the different parts of the cell communicate. DOI: http://dx.doi.org/10.7554/eLife.03558.002
- Published
- 2014