Mitochondrial trafficking and morphology in healthy and injured neurons

doi:10.1016/j.pneurobio.2006.09.003

Progress in Neurobiology

Volume 80, Issue 5, December 2006, Pages 241-268

https://doi.org/10.1016/j.pneurobio.2006.09.003 Get rights and content

Abstract

Mitochondria are the primary generators of ATP and are important regulators of intracellular calcium homeostasis. These organelles are dynamically transported along lengthy neuronal processes, presumably for appropriate distribution to cellular regions of high metabolic demand and elevated intracellular calcium, such as synapses. The removal of damaged mitochondria that produce harmful reactive oxygen species and promote apoptosis is also thought to be mediated by transport of mitochondria to autophagosomes. Mitochondrial trafficking is therefore important for maintaining neuronal and mitochondrial health while cessation of movement may lead to neuronal and mitochondrial dysfunction. Mitochondrial morphology is also dynamic and is remodeled during neuronal injury and disease. Recent studies reveal different manifestations and mechanisms of impaired mitochondrial movement and altered morphology in injured neurons. These are likely to cause varied courses toward neuronal degeneration and death. The goal of this review is to provide an appreciation of the full range of mitochondrial function, morphology and trafficking, and the critical role these parameters play in neuronal physiology and pathophysiology.

Introduction

Mitochondria in most cells are highly dynamic organelles that fuse, divide, move and replicate, and are associated with a finite lifetime that is typically shorter than the life of the host cell. In this review, we will focus on these dynamics in the context of neurons. In most respects we anticipate that the basic functional properties of mitochondria in neurons resemble those in other cell types. However, the challenges posed by having to move organelles over extreme distances, and also to maintain cellular homeostasis in very large and highly active cells are unique to neurons, making mitochondrial function in these cells of particular interest. Mitochondrial dynamics in neurons is a fundamental but highly complex property with broad implications for normal and abnormal cellular and mitochondrial function. Mitochondrial movement is intimately tied with the functional status of cells and of the organelles themselves (Malaiyandi et al., 2005, Reynolds and Santos, 2005, Rintoul et al., 2003a, Rintoul et al., 2003b, Stout et al., 1998). Additionally, the consequences of dynamic changes in mitochondrial morphology under physiological and injurious conditions require further study (Frank et al., 2001, Rintoul et al., 2003a, Szabadkai et al., 2004, Yu et al., 2006). In this review, we discuss normal mitochondrial physiology, mitochondrial dysfunction in neuronal injury and disease, the importance of mitochondrial trafficking and morphology in neuronal health, mechanisms that regulate mitochondrial movement and morphology, and current and future approaches to studying mitochondrial trafficking.

Since appropriate mitochondrial delivery is critical to neuronal health, it is not surprising that impaired mitochondrial trafficking can contribute to pathophysiology. Recent studies implicate aberrant mitochondrial movement in multiple neuronal injuries and diseases (Chang et al., 2006a, Chang et al., 2006b, Ebneth et al., 1998, Malaiyandi et al., 2005, Piccioni et al., 2002, Rintoul et al., 2003a, Sasaki et al., 2005). However, it is becoming clear that trafficking impairment can have diverse manifestations that likely contribute to different patterns of neurodegeneration and cell death. In the second part of this review, we discuss causes and consequences of impaired mitochondrial movement, and manifestations and mechanisms of heterogeneous movement abnormalities in neurons. Lastly, we consider what the future will uncover about mitochondrial trafficking and how that knowledge can be harnessed to develop pharmacologic therapies for neuronal injury and disease.

Section snippets

Importance of mitochondria in brain

Mitochondria are vital organelles for cell survival. They are the primary generators of cellular energy and they accomplish this with great efficiency. By coupling electron transport to the generation of proton gradients for oxidative phosphorylation, mitochondria produce approximately 15 times more ATP from glucose than the glycolytic pathway in eukaryotic cells. Cells of highly metabolic tissues such as muscle, liver and brain, are therefore particularly dependent on mitochondria.

Evolution and biogenesis of mitochondria

Mitochondria in eukaryotic organisms are thought to be the result of engulfment of aerobically respiring prokaryotic organisms 1.5 × 10⁹ years ago. A symbiotic relationship was then forged whereby mitochondria were able to rely on the host cell for transcription and protein synthesis and the host adopted efficient energy production (Gray, 1993). Therefore, while present-day mitochondria still have their own circular double-stranded genomes and protein synthetic machinery, evolution probably

Mitochondrial morphology

Mitochondrial morphology is diverse and dynamic, varying between different cell types, within individual cells, and under different cellular environments. We observed changes in mitochondrial morphology as cortical neurons develop synaptic connections, and between axons and dendrites of mature neurons (Fig. 1, Fig. 2A and B). Popov et al. (2005) reported similar findings of filamentous dendritic mitochondria compared to discrete axonal mitochondria in hippocampal slices prepared from rats and

Significance of mitochondrial transport: focus on synapses

Mitochondrial movement has been described for many years (Lewis and Lewis, 1914), but is assisted these days by fluorescent labels for mitochondria in live cells, time-lapse microscopy and genetic mutants with abnormal trafficking patterns. These techniques are used to study patterns of mitochondrial movement, mechanisms of mitochondrial transport, and perhaps most importantly, cellular and mitochondrial signals that dynamically govern mitochondrial trafficking. Anterograde and retrograde

Patterns of mitochondrial movement

Mitochondrial movement in neurons is highly diverse and complex (vide infra; Chang et al., 2006a, Chang and Reynolds, 2006, Ligon and Steward, 2000a, Morris and Hollenbeck, 1995, Morris and Hollenbeck, 1993, Overly et al., 1996). Some mitochondria appear stationary whereas others are motile. Motile mitochondria not only move with different speeds and in different directions, but they exhibit saltatory movement, making stops along their trajectory. These stops are also variable. Mitochondria can

Adopting a reductionist approach to studying mitochondrial trafficking

Mitochondrial movement in neurons is extremely diverse with velocity, direction changes and pauses during movement varying between individual organelles, different neuronal processes, and different cells. There is also likely to be variability in the regulatory influences on movement between individual mitochondria such that: (i) they may be targeted to different cues in cells, (ii) these cues may have various distributions in different neuronal processes, (iii) the characteristics of motor and

Relationship between mitochondrial movement and mitochondrial and cellular injury

The close relationship between mitochondrial movement, mitochondrial health and cell health dictates that impairment of any one of these properties can negatively impact the other two properties (Fig. 7). As discussed in Sections 6.2 Mechanisms of mitochondrial movement, 7.2.2 Studying mitochondrial movement responses to global pharmacologic treatments, mitochondrial movement in neurons is sensitive to changes in mitochondrial functional status, as well as to changes in the cellular environment

Manifestations and mechanisms of mitochondrial movement impairment

Cessation of mitochondrial movement can have diverse manifestations in a single injured or diseased neuron. In some cases, all mitochondria may be equally exposed to pathologic conditions that impair movement. In others, sources of injury may localize to specific neuronal regions, producing spatially restricted transport defects. Variability in axonal and dendritic physiology and in proteins and signals that mediate transport of individual mitochondria can also contribute to heterogeneous

Complex mitochondrial movement impairments in neuronal injury and disease

Axonal transport is impaired in multiple neurodegenerative conditions and it is clear that mitochondria are affected cargos. Possible causes of impaired transport in neurons include mitochondrial injury, [Ca²⁺]_i disturbance, oxidative stress, mutations in motor proteins, defects in proteins that regulate or interact with motor proteins, and nonspecific disease processes such as protein aggregation that may block transport. Mitochondria represent a special cargo because transport is related to

Conclusions

While a lot is known about mitochondrial physiology and cell survival and death mechanisms in neurons, we are only beginning to understand mitochondrial trafficking. Despite all the complexities, research in the last decade produced detailed descriptions of movement patterns, identified potential targets and functional roles for mitochondrial trafficking, and implicated disrupted mitochondrial transport in neuronal injury and degeneration. Efficient progress is largely contributed by the

Acknowledgement

This work was supported by NIH grant NS049560.

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Mitochondrial trafficking and morphology in healthy and injured neurons

Abstract

Introduction

Section snippets

Importance of mitochondria in brain

Evolution and biogenesis of mitochondria

Mitochondrial morphology

Significance of mitochondrial transport: focus on synapses

Patterns of mitochondrial movement

Adopting a reductionist approach to studying mitochondrial trafficking

Relationship between mitochondrial movement and mitochondrial and cellular injury

Manifestations and mechanisms of mitochondrial movement impairment

Complex mitochondrial movement impairments in neuronal injury and disease

Conclusions

Acknowledgement

Neuron

Curr. Biol.

Toxicol. Appl. Pharmacol.

Trends Cell Biol.

Trends Cell Biol.

Int. Rev. Cytol.

Neuropharmacology

Cell Calcium

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

Neuropharmacology

FEBS Lett.

Curr. Biol.

Neuroscience

Neurobiol. Dis.

Mol. Cell

Free Radic. Biol. Med.

Cell

Mol. Asp. Med.

J. Biol. Chem.

Prog. Neurobiol.

FEBS Lett.

Dev. Cell

J. Biol. Chem.

J. Biol. Chem.

Gene

Neurobiol. Aging

Curr. Opin. Genet. Dev.

J. Biol. Chem.

J. Biol. Chem.

Curr. Biol.

Neuron

Neuron

Neuron

Neuron

Biochem. Biophys. Res. Commun.

Curr. Biol.

Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells

J. Cell Biol.

Oxidative stress in neurodegeneration: cause or consequence?

Nat. Rev. Neurosci.

Mitochondrial metabolism of reactive oxygen species

Biochemistry (Mosc.)

Rapid remodeling of axonal arbors in the visual cortex

Science

Fructose prevents hypoxic cell death in liver

Am. J. Physiol. Gastrointest. Liver Physiol.

Apoptosis in mitochondrial myopathies is linked to mitochondrial proliferation

Brain

Changes in microtubule polarity orientation during the development of hippocampal neurons in culture

J. Cell Biol.

Mitochondrial participation in the intracellular Ca2+ network

J. Cell Biol.

Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death

Nature

Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid

J. Neurosci.

Involvement of mitochondrial complex II defects in neuronal death produced by N-terminus fragment of mutated huntingtin

Mol. Biol. Cell

Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis

J. Neurochem.

Mitochondrial participation in the intracellular Ca²⁺ network