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Review
, 9 (7), 505-18

Mitochondrial Fragmentation in Neurodegeneration

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Review

Mitochondrial Fragmentation in Neurodegeneration

Andrew B Knott et al. Nat Rev Neurosci.

Abstract

Mitochondria are remarkably dynamic organelles that migrate, divide and fuse. Cycles of mitochondrial fission and fusion ensure metabolite and mitochondrial DNA mixing and dictate organelle shape, number and bioenergetic functionality. There is mounting evidence that mitochondrial dysfunction is an early and causal event in neurodegeneration. Mutations in the mitochondrial fusion GTPases mitofusin 2 and optic atrophy 1, neurotoxins and oxidative stress all disrupt the cable-like morphology of functional mitochondria. This results in impaired bioenergetics and mitochondrial migration, and can trigger neurodegeneration. These findings suggest potential new treatment avenues for neurodegenerative diseases.

Figures

Figure 1
Figure 1. Neuronal mitochondria
Each neuron contains several hundred mitochondria that form cable-like structures along neuronal projections to help them meet their large energy demands. Neurons require energy to transport organelles and cargo along microtubules or actin fibres (motor molecules like dyneins, kinesins and myosin mediate this process) and to maintain ion gradients and the membrane potential by ATP-dependent Ca2+ and Na+/K+ pumps and ion channels. Additionally, neurotransmitter vesicle loading at pre-synaptic terminals and Ca2+-mediated neurotransmitter release into the synaptic cleft are also ATP-dependent events. Glutamate transporters mediate glutamate re-uptake from the synaptic cleft, and at the post-synaptic membrane, glutamate binding to NMDA receptors evokes Ca2+ influx, which in turn can activate Nitric Oxide Synthase (NOS) and stimulate the generation of Nitric Oxide (NO). Both, NO and Ca2+ can directly modulate mitochondrial function by altering the levels of ROS (H2 O2 and O2-) and ATP production.(b) Fluorescence 3D microscope image of mitochondria in a dendritic arbor of a neuron expressing DsRed-Mito, a red fluorescent fusion protein targeted selectively to the mitochondrial matrix (scale bar:5 μm). (c) Slice through an EM tomographic volume showing a mitochondrion in a neuronal process. Mitochondrial length is typically 2-25 μm in neurites with a diameter of 0.5 μm (scale bar: 400 nm). Shown underneath is a view of the surface-rendered volume after segmentation of the same mitochondrion. The outer membrane is a translucent pale blue and individual cristae are shown in different colors.
Figure 2
Figure 2. Mitochondrial fusion
(a) Mitochondrial outer membrane fusion occurs by homotypic Mfn2 interaction in trans across two mitochondria. It is possible that Mfn2 mediates outer membrane fusion by binding to and forming clusters at mitochondrial tips - the ends of the tubular organelles. (b) Domain model of Mfn2 showing the conserved GTPase domain and the proposed Neck, Trunk, and Paddle/Tip regions. Ribbon diagram of the bacterial dynamin-like protein (BDLP) homodimer shown with one molecule in gray and the other rainbow color-coded from N (blue) to C (red) terminus. Mfn2 cartoon based on the BDLP structure indicating proposed GTPase (magenta), Neck (green), Trunk (cyan), and Paddle (red) regions. (c) Proposed model of potential buckle and molecular zippering mechanism for Mfn2-mediated mitochondrial fusion. The Mfn2 dimer grabs adjacent mitochondrial outer membranes with its hydrophobic paddle domain and fuses them through a conformational change (induced by GTP hydrolysis) of its trunk and paddle region. Other regulatory proteins are likely to be involved. (d) OPA1-mediated inner membrane fusion. Mitochondrial matrix contents mix after inner membrane fusion. (e) Domain model of OPA1 (Swissprot: O60313) showing location of the mitochondrial targeting sequence (MTS), TM transmembrane region, GTPase domain, helical domain, and putative GED domain.
Figure 3
Figure 3. Mitochondrial fission
(a) Drp1 is found in the cytoplasm, but cycles on and off mitochondria, possibly by indirect interaction with the outer-membrane associated hFis1. Once bound to the mitochondrial outer membrane, Drp1 forms large clusters or foci, which mediate membrane fission. OM indicates the outer membrane and IM indicates the inner membrane. (b) Domain model of Drp1 (Swissprot: O00429) showing the conserved GTPase domain, helical domain, and GTP effector domain (GED). (c) Fluorescent 3D microscopic image of a fused, elongated mitochondrion (red) in a healthy neuron and round, fissioned mitochondria in a neuron exposed to nitrosative stress. The mitochondrial labeling results from DsRed-Mito expression.(d) Slice through an EM tomographic volume showing four fragmented mitochondria (indicated by arrows) in a neuronal process after exposure to an NO donor, which triggers mitochondrial fission. Mitochondria are recognizable because of their cristae structure, even with some cristae membrane degradation. (e) Top view of the surface-rendered volume after segmentation of the same four mitochondria as shown in (d). The outer membrane is shown in pale blue and the cristae in various colors. Cristae fragmentation is evident from the smaller and regionally confined cristae. (f) Side view of the surface-rendered volume. The outer membrane is made transparent to better visualize the cristae. Fission induces a profound remodeling of the inner membrane with cristae vesiculation.
Figure 4
Figure 4. Mutations in Mfn2 and OPA1 present in human patients
(a) Domain model of Mfn2 (Swissprot: O95140) showing location of the GTPase domain and the putative Neck, Trunk, and Paddle domains. Red arrows indicate locations of missense mutations found in CMT-2A patients (OMIM database: 608507). (b) Homology model of human Mfn2 residues 24-757 shown in ribbon presentation, indicating the GTPase, Neck, Tip, Paddle, and Trunk region based on the crystal structure of bacterial dynamin-like protein (PDB-ID 2j68 (2), FFAS (1) score - 67.0, sequence identity 11%). Red spheres indicate mutations found in CMT2A. (c) Domain model of OPA1 with locations of missense mutations found in ADOA patients (top) (OMIM database: 165500) indicated by red arrows and ‘OPA1-plus’ disorders (bottom) indicated by black arrows. (d) Homology model of the OPA1 GTPase domain (residues 244-575) based on the dynamin GTPase domain (1jw1.pdb) shown in ribbon representation with a GDP molecule bound in the putative active site shown in ball and stick. Red spheres indicate residues mutated in ADOA patients (eOPA1)5. A close up view of the active site in OPA-1 shows native (gray) and mutant (yellow) side-chains for comparison. The model clearly shows that several mutations directly interfere with GTP binding and most probably impair the catalytic function. Models were prepared with PyMOL (DeLano Scientific).
Figure 5
Figure 5. Gene shift and exercise
Model of how exercise might reduce the prevalence of mtDNA point mutations in muscle cells through gene shift. Satellite cells, undifferentiated cells found in mature muscle, possess wild-type mtDNA. Exercise stimulates differentiation and growth of satellite cells. When wild-type satellite cells fuse with muscle cells carrying mtDNA point mutations, mitochondria mix and fuse. Fusion of mitochondria allows wild-type mtDNA from satellite cells to compensate for mutant mtDNA, decreasing the prevalence of mtDNA mutations.

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