Mitochondrial dynamics in neuronal injury, development and plasticity

Abstract

Mitochondria fulfill numerous cellular functions including ATP production, Ca²⁺ buffering, neurotransmitter synthesis and degradation, ROS production and sequestration, apoptosis and intermediate metabolism. Mitochondrial dynamics, a collective term for the processes of mitochondrial fission, fusion and transport, governs mitochondrial function and localization within the cell. Correct balance of mitochondrial dynamics is especially important in neurons as mutations in fission and fusion enzymes cause peripheral neuropathies and impaired development of the nervous system in humans. Regulation of mitochondrial dynamics is partly accomplished through post-translational modification of mitochondrial fission and fusion enzymes, in turn influencing mitochondrial bioenergetics and transport. The importance of post-translational regulation is highlighted by numerous neurodegenerative disorders associated with post-translational modification of the mitochondrial fission enzyme Drp1. Not surprisingly, mitochondrial dynamics also play an important physiological role in the development of the nervous system and synaptic plasticity. Here, we highlight recent findings underlying the mechanisms and regulation of mitochondrial dynamics in relation to neurological disease, as well as the development and plasticity of the nervous system.

Keywords: Bioenergetics; Dynamin-related protein 1; Mitochondrial fission; Mitochondrial fusion; Neurodegenerative disease; Synaptic plasticity.

Fig. 1.

GTPases catalyze mitochondrial fission and fusion. Mitochondrial fission occurs through oligomerization of active Drp1 and constriction of the outer mitochondrial membrane (OMM). The mitochondrial adaptor protein Mff appears to be important for coordinating the oligomerization of active Drp1, whereas Mid49 and Mid51 are thought to localize inactive Drp1 to the OMM in preparation for future fission events. Mitochondrial fusion requires the coordination of mitofusin1 and 2 (Mfn1and Mfn2) at the OMM, and Opa1 at the inner mitochonrdrial membrane (IMM). Homo- or heterodimerization of Mfn1 and Mfn2 on opposing OMM surfaces promote fusion of the OMM. Similarly, homodimerization of Opa1 at the IMM promotes fusion of mitochondrial matrix compartments.

Fig. 2.

Post-translation modification (PTM) of mitochondrial fission and fusion proteins. (A) Drp1 can undergo a variety of PTMs, leading to either fission of fusion of mitochondria. PTMs of most other mitochondrial fission and fusion proteins appear to result exclusively in fission; however, the characterization of their PTMs is far from comprehensive. (B) Location of Drp1 S616 and S637 (human isoform 1) in different Drp1 splice variants and the inclusion of alternative exons based on the PhosphoSitePlus database (http://www.phosphosite.org/homeAction.action) (Hornbeck et al., 2015).

Fig. 3.

Neuroprotective effects of inhibiting mitochondrial fission through inhibition of Drp1. During cerebral ischemia, mitochondrial fission occurs and has been proposed to contribute to ischemic injury as inhibition of Drp1; thus, mitochondrial fission attenuates neuron death. However, inhibition of Drp1 does not prevent hypoxia or glutamate-mediated mitochondrial fission, suggesting the protective effect of Drp1 inhibition is due to increased connectivity of the mitochondrial network prior to ischemic insult. Essentially, the promotion of mitochondrial fusion by inhibiting Drp1 improves the bioenergetic capacity of mitochondria, which in turn prevents bioenergetic deficiency and collapse of ionic homeostasis that is normally observed during glutamate excitotoxicity and hypoxia. Here, the ability to maintain ionic homeostasis until reperfusion is presumed to prevent neuron death.

Fig. 4.

Mitochondrial fission and fusion impact on dendritic spine development. Promotion of mitochondrial fusion or fission, respectively, increases or decreases the mitochondrial membrane potential (Ψm), indicated by small green or red arrow, respectively. In turn, an increase or decrease of Ψm presumably increases or decreases mitochondrial Ca²⁺ buffering, respectively. (A) Reduced mitochondrial Ca²⁺ buffering as a result of mitochondrial fission likely increases cytosolic Ca²⁺ levels (thick blue arrow), thereby augmenting dendritic spine development (bold green bracket) through activation of Ca²⁺-sensitive transcriptional reprogramming. (B) In contrast, increased mitochondrial Ca²⁺ buffering as a result of fusion likely decreases cytosolic Ca²⁺ concentration (thin blue arrow), thereby impairing synaptic activity-dependent dendritic spine development (thin red bracket) through decreased activation of Ca²⁺-dependent transcriptional programs (thin red arrow).

Fig. 5.

Mitochondrial dynamics in synaptic transmission. Multiple mitochondrial functions are necessary for correct synaptic function. (1) Presynaptic mitochondrial Ca²⁺ buffering during high frequency stimulation allows for controlled and sustained release of Ca²⁺, thereby improving the release efficiency of neurotransmitters (e.g. glutamate). (2) Presynaptic mitochondrial ATP production supports synaptic vesicle recycling and mobilization of the reserve vesicle pool, both of which allow for sustained neurotransmitter release during high frequency stimulation. (3) Postsynaptic mitochondrial Ca²⁺ buffering is necessary to induce LTP in the hippocampus and the spinal cord. (4) Postsynaptic mitochondrial ATP production is also important to induce LTP, given that mitochondrial ATP production is inhibited in response to rotenone, thereby impairing hippocampal LTP during high frequency stimulation. (5) Inhibition of Drp1 and mitochondrial fission impairs activity-dependent transport of mitochondria to synapses both pre- and postsynaptically. However, it is important to note that multiple studies suggest that terminals and spines that lack mitochondria are still capable of maintaining basal synaptic transmission.