Synapses enable neurons to communicate with each other and are therefore a prerequisite for normal brain function. Presynaptically, this communication requires energy and generates large fluctuations ...in calcium concentrations. Mitochondria are optimized for supplying energy and buffering calcium, and they are actively recruited to presynapses. However, not all presynapses contain mitochondria; thus, how might synapses with and without mitochondria differ? Mitochondria are also increasingly recognized to serve additional functions at the presynapse. Here, we discuss the importance of presynaptic mitochondria in maintaining neuronal homeostasis and how dysfunctional presynaptic mitochondria might contribute to the development of disease.
In the current model of mitochondrial trafficking, Miro1 and Miro2 Rho‐GTPases regulate mitochondrial transport along microtubules by linking mitochondria to kinesin and dynein motors. By generating ...Miro1/2 double‐knockout mouse embryos and single‐ and double‐knockout embryonic fibroblasts, we demonstrate the essential and non‐redundant roles of Miro proteins for embryonic development and subcellular mitochondrial distribution. Unexpectedly, the TRAK1 and TRAK2 motor protein adaptors can still localise to the outer mitochondrial membrane to drive anterograde mitochondrial motility in Miro1/2 double‐knockout cells. In contrast, we show that TRAK2‐mediated retrograde mitochondrial transport is Miro1‐dependent. Interestingly, we find that Miro is critical for recruiting and stabilising the mitochondrial myosin Myo19 on the mitochondria for coupling mitochondria to the actin cytoskeleton. Moreover, Miro depletion during PINK1/Parkin‐dependent mitophagy can also drive a loss of mitochondrial Myo19 upon mitochondrial damage. Finally, aberrant positioning of mitochondria in Miro1/2 double‐knockout cells leads to disruption of correct mitochondrial segregation during mitosis. Thus, Miro proteins can fine‐tune actin‐ and tubulin‐dependent mitochondrial motility and positioning, to regulate key cellular functions such as cell proliferation.
Synopsis
Miro1 and Miro2 coordinate specific and overlapping functions to regulate microtubule‐ and actin‐dependent mitochondrial trafficking. This coordination is critical to ensure correct mitochondrial segregation during cell division.
Miro proteins are differentially required in different stages of embryonic development.
Miro proteins are not essential for TRAK/kinesin‐mediated anterograde mitochondrial movement.
Miro1 regulates TRAK2‐dependent mitochondrial retrograde transport.
Miro proteins recruit and stabilize mitochondrial myosin Myo19 on the outer mitochondrial membrane to mediate actin‐based mitochondrial movements.
Miro proteins coordinate tubulin‐ and actin‐mediated mitochondrial movement to regulate equal segregation of mitochondria during mitosis.
In addition to controlling mitochondrial retrograde trafficking along microtubules, Miro GTPases also mediate actin‐dependent movements via recruitment of mitochondrial myosin 19.
Mitochondria play an essential role in ATP generation, calcium buffering and apoptotic signalling. In neurons, the transport of mitochondria to specific locations where they are needed has emerged as ...an important process for correct nerve cell function. Recent studies have shed light on the mechanisms that control mitochondrial transport and localization in neurons. We describe the machinery that is important for constitutive transport of mitochondria throughout the cell, and highlight recent advances in our understanding of how signalling pathways can converge on this machinery and allow for rapid activity-dependent control of mitochondrial trafficking and localization. Regulation of mitochondrial trafficking might work in concert with mitochondrial tethering systems to give precise control of mitochondrial delivery and localization to regions of high energy and calcium buffering requirements within neurons.
Mitochondrial Rho (Miro) GTPases localize to the outer mitochondrial membrane and are essential machinery for the regulated trafficking of mitochondria to defined subcellular locations. However, ...their sub-mitochondrial localization and relationship with other critical mitochondrial complexes remains poorly understood. Here, using super-resolution fluorescence microscopy, we report that Miro proteins form nanometer-sized clusters along the mitochondrial outer membrane in association with the Mitochondrial Contact Site and Cristae Organizing System (MICOS). Using knockout mouse embryonic fibroblasts we show that Miro1 and Miro2 are required for normal mitochondrial cristae architecture and Endoplasmic Reticulum-Mitochondria Contacts Sites (ERMCS). Further, we show that Miro couples MICOS to TRAK motor protein adaptors to ensure the concerted transport of the two mitochondrial membranes and the correct distribution of cristae on the mitochondrial membrane. The Miro nanoscale organization, association with MICOS complex and regulation of ERMCS reveal new levels of control of the Miro GTPases on mitochondrial functionality.
Correct mitochondrial distribution is critical for satisfying local energy demands and calcium buffering requirements and supporting key cellular processes. The mitochondrially targeted proteins ...Miro1 and Miro2 are important components of the mitochondrial transport machinery, but their specific roles in neuronal development, maintenance, and survival remain poorly understood. Using mouse knockout strategies, we demonstrate that Miro1, as opposed to Miro2, is the primary regulator of mitochondrial transport in both axons and dendrites. Miro1 deletion leads to depletion of mitochondria from distal dendrites but not axons, accompanied by a marked reduction in dendritic complexity. Disrupting postnatal mitochondrial distribution in vivo by deleting Miro1 in mature neurons causes a progressive loss of distal dendrites and compromises neuronal survival. Thus, the local availability of mitochondrial mass is critical for generating and sustaining dendritic arbors, and disruption of mitochondrial distribution in mature neurons is associated with neurodegeneration.
Display omitted
•Miro1 deletion alters mitochondrial distribution in dendrites but not axons•Mitochondrial distribution impacts dendritic development•Correct mitochondrial distribution is key to maintain complex dendritic geometries•Aberrant dendritic mitochondrial distribution triggers neurodegeneration
Complex dendritic morphologies are essential for neural circuit formation and brain computation. López-Doménech et al. demonstrate that Miro1-dependent dendritic mitochondrial positioning critically regulates the development of the dendritic tree and sustains arborization. Disrupting mitochondrial distribution in mature neurons leads to the loss of dendritic complexity, which precedes neurodegeneration.
Mitochondrial trafficking is influenced by neuronal activity, but it remains unclear how mitochondrial positioning influences neuronal transmission and plasticity. Here, we use live cell imaging with ...the genetically encoded presynaptically targeted Ca2+ indicator, SyGCaMP5, to address whether presynaptic Ca2+ responses are altered by mitochondria in synaptic terminals. We find that presynaptic Ca2+ signals, as well as neurotransmitter release, are significantly decreased in terminals containing mitochondria. Moreover, the localisation of mitochondria at presynaptic sites can be altered during long‐term activity changes, dependent on the Ca2+‐sensing function of the mitochondrial trafficking protein, Miro1. In addition, we find that Miro1‐mediated activity‐dependent synaptic repositioning of mitochondria allows neurons to homeostatically alter the strength of presynaptic Ca2+ signals in response to prolonged changes in neuronal activity. Our results support a model in which mitochondria are recruited to presynaptic terminals during periods of raised neuronal activity and are involved in rescaling synaptic signals during homeostatic plasticity.
Synopsis
Miro1‐dependent relocalisation of mitochondria to the presynapse permits buffering of Ca2+ via the mitochondrial calcium uniporter (MCU) and attenuates vesicular release. This mechanism allows neurons to modulate synaptic Ca2+ signals in response to long‐term changes in network activity.
Mitochondria located at neuronal presynapses buffer Ca2+ signals, thereby attenuating vesicular release triggered by action potentials.
Mitochondria are dynamically recruited to and from presynapses in response to long‐term network activity changes, dependent on the Ca2+‐sensing function of the mitochondrial trafficking protein Miro1.
This repositioning of mitochondria enables neurons to modulate synaptic Ca2+ signals during homeostatic plasticity.
Miro1‐dependent relocalisation of mitochondria to the presynapse permits buffering of Ca2+ via the mitochondrial calcium uniporter (MCU) and attenuates vesicular release. This mechanism allows neurons to modulate synaptic Ca2+ signals in response to long‐term changes in network activity.
Correct mitochondrial dynamics are essential to neuronal function. These dynamics include mitochondrial trafficking and quality-control systems that maintain a precisely distributed and healthy ...mitochondrial network, so that local energy demands or Ca2+-buffering requirements within the intricate architecture of the neuron can be met. Mitochondria make use of molecular machinery that couples these organelles to microtubule-based transport via kinesin and dynein motors, facilitating the required long-range movements. These motors in turn are associated with a variety of adaptor proteins allowing additional regulation of the complex dynamics demonstrated by these organelles. Over recent years, a number of new motor and adaptor proteins have been added to a growing list of components implicated in mitochondrial trafficking and distribution. Yet, there are major questions that remain to be addressed about the regulation of mitochondrial transport complexes. One of the core components of this machinery, the mitochondrial Rho GTPases Miro1 (mitochondrial Rho 1) and Miro2 have received special attention due to their Ca2+-sensing and GTPase abilities, marking Miro an exceptional candidate for co-ordinating mitochondrial dynamics and intracellular signalling pathways. In the present paper, we discuss the wealth of literature regarding Miro-mediated mitochondrial transport in neurons and recently highlighted involvement of Miro proteins in mitochondrial turnover, emerging as a key process affected in neurodegeneration.
Peroxisomes are organelles that perform a wide range of essential metabolic processes. To ensure that peroxisomes are optimally positioned in the cell, they must be transported by both long- and ...short-range trafficking events in response to cellular needs. Here, we review our current understanding of the mechanisms by which the cytoskeleton and organelle contact sites alter peroxisomal distribution. Though the focus of the review is peroxisomal transport in mammalian cells, findings from flies and fungi are used for comparison and to inform the gaps in our understanding. Attention is given to the apparent overlap in regulatory mechanisms for mitochondrial and peroxisomal trafficking, along with the recently discovered role of the mitochondrial Rho-GTPases, Miro, in peroxisomal dynamics. Moreover, we outline and discuss the known pathological and pharmacological conditions that perturb peroxisomal positioning. We conclude by highlighting several gaps in our current knowledge and suggest future directions that require attention.
Binding of motor proteins to cellular cargoes is regulated by adaptor proteins. HAP1 and GRIP1 are kinesin-1 adaptors that have been implicated individually in the transport of vesicular cargoes in ...the dendrites of neurons. We find that HAP1a and GRIP1 form a protein complex in the brain, and co-operate to activate the kinesin-1 subunit KIF5C
Based upon this co-operative activation of kinesin-1, we propose a modification to the kinesin activation model that incorporates stabilisation of the central hinge region known to be critical to autoinhibition of kinesin-1.
Altered excitatory/inhibitory (E/I) balance is implicated in neuropsychiatric and neurodevelopmental disorders, but the underlying genetic etiology remains poorly understood. Copy number variations ...in CYFIP1 are associated with autism, schizophrenia, and intellectual disability, but its role in regulating synaptic inhibition or E/I balance remains unclear. We show that CYFIP1, and the paralog CYFIP2, are enriched at inhibitory postsynaptic sites. While CYFIP1 or CYFIP2 upregulation increases excitatory synapse number and the frequency of miniature excitatory postsynaptic currents (mEPSCs), it has the opposite effect at inhibitory synapses, decreasing their size and the amplitude of miniature inhibitory postsynaptic currents (mIPSCs). Contrary to CYFIP1 upregulation, its loss in vivo, upon conditional knockout in neocortical principal cells, increases expression of postsynaptic GABAA receptor β2/3-subunits and neuroligin 3, enhancing synaptic inhibition. Thus, CYFIP1 dosage can bi-directionally impact inhibitory synaptic structure and function, potentially leading to altered E/I balance and circuit dysfunction in CYFIP1-associated neurological disorders.
Display omitted
•CYFIP1 and CYFIP2 are enriched at inhibitory synapses.•CYFIP1 upregulation differentially disrupts inhibitory and excitatory synapses.•Conditional loss of CYFIP1 alters neuroligin 3 and GABAAR β-subunits expression.•Loss of CYFIP1 increases inhibitory synaptic clusters and hence mIPSC amplitude.
Copy number variations (CNVs) in CYFIP1 are associated with neuropsychiatric disorders. Davenport et al. uncover an essential role for CYFIP1 in regulating synaptic inhibition and in maintaining the excitatory/inhibitory balance. By altering CYFIP1 gene dosage, to model CNV, they reveal important bi-directional effects on inhibitory transmission in hippocampal neurons.
PDF
