The Mechanism of Kinesin Regulation by Ca++ for Control of Mitochondrial Motility

By Xinnan Wang, Thomas Schwarz. Cell, 2009

889 citations recorded by the source corpus.

SUMMARY Cells regulate mitochondrial movement in order to distribute mitochondria properly and thereby meet the changing energy needs of each region of the cell. Ca++ signaling, which halts both anterograde and retrograde mitochondrial motion, is one such regulation. We show that the EF-hands of Miro mediate this arrest and elucidate the regulatory mechanism of the motor kinesin-1. Kinesin-1 remains on mitochondria whether they are stationary, moving anterograde, or moving retrograde and the protein complex that couples kinesin-1 to mitochondria is not dissociated by elevated Ca++. Instead, Ca++-binding to Miro permits Miro to interact directly with the motor domain, thereby preventing motor/microtubule interactions. This switching mechanism allows Ca++ to regulate mitochondrial motility via two kinesin states: an active state in which kinesin is bound to mitochondria via its tail and milton, and an inactive state in which the motor domain binds directly Miro. Disrupting this regulation diminishes neuronal resistance to excitotoxicity.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/edff4092b6fd1f53c7f38d26c670ea8ba66a2b15

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Citations in the corpus

Miro1 Is a Calcium Sensor for Glutamate Receptor-Dependent Localization of Mitochondria at Synapses (2009, neutral): “Wang and Schwarz (2009) suggested that Miro does not interact directly with KIF5, as we have shown in Figure 2, but requires a mammalian homolog of Drosophila Milton as an adaptor, although they did report a low level of Miro-KIF association without Drosophila Milton present.”
Metabolic regulation of mitochondrial dynamics (2016, background): “Kinesin-1 attaches to mitochondria via its adaptor (Milton) and receptor (Miro).”
The axonal transport of mitochondria (2005, background): “When Ca levels are elevated, a conformational change is induced in the Ca-binding EF hand domains of Miro that causes it to bind the Khc motor domains, thereby blocking Khc binding to microtubules, but leaving the Miro–Milton–Khc complex on the mitochondrial surface (Wang and Schwarz, 2009).”
Cross Talk Between O-GlcNAcylation and Phosphorylation: Roles in Signaling, Transcription, and Chronic Disease (2011, background): “Examples of OGT targeting proteins include Milton (OIP106) (75, 76), which is important for mitochondrial and receptor translocation in nerve axons; p38 MAP kinase, which plays a role in the dramatic increased O-GlcNAcylation of a subset of proteins during glucose starvation of nerve cells (70); the”
Synaptic energy use and supply. (2012, positive): “Wang and Schwarz (2009) found that a rise in axonal [Ca2+]i in hippocampal neurons leads to mitochondrial stopping, following Ca2+ binding to the adaptor protein Miro, which resulted in kinesin motors detaching from their microtubule tracks (Figure 5, presynaptic side; Ca2+ entry into the…”
Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration (2012, background): “or to elevated neuronal Ca 2+ levels caused by the application of the calcium ionophore calcimyci”
Mitochondria: In Sickness and in Health (2012, background): “Consistent with this model, the EF hands of Miro mediate glutamatergic regulation of mitochondrial motility and provide a protective mechanism against excitotoxicity (Wang and Schwarz, 2009).”
AXONAL TRANSPORT: CARGO-SPECIFIC MECHANISMS OF MOTILITY AND REGULATION (2014, background): “Elevated intracellular calcium levels resulting from enhanced synaptic activity arrestmitochondrial motility in a highly localized fashion, since mitochondria as little as 15 mm away from the stimulation site remain motile (Li et al., 2004; Macaskill et al., 2009b; Wang and Schwarz, 2009).”
Aβ Oligomers Cause Localized Ca2+ Elevation, Missorting of Endogenous Tau into Dendrites, Tau Phosphorylation, and Destruction of Microtubules and Spines (2010, background): “Thirdly, Ca 2 uncouples mitochondrial motors from microtubule tracks (Wang and Schwarz, 2009).”
Mechanisms of mesenchymal stem/stromal cell function (2016, background): “Wang and Schwartz [135] elegantly demonstrated that Ca promotes Miro to interact with the motor domain of kinesin, thus blocking kinesin from the microtubule.”
Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease. (2010, positive): “One model has suggested that Ca 2+ binding to the Miro EF hand turns off KIF5 engagement with microtubules (Wang and Schwarz, 2009; Figure 6C).”