What Is the Role of Mitochondrial Fission in Neurologic Disease?

Benarroch, Eduardo E.

doi:10.1212/wnl.0000000000200233

Cited by 3 publications

(3 citation statements)

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“…In non-dividing cells, such as neurons, mitochondrial fusion and fission balance is essential to regulate mitochondrial size, number, morphology and proper turnover via biogenesis and mitophagy. Furthermore, in neurons, mitochondrial fission is required for efficient transport of mitochondria to the axon, since the trafficking of smaller organelles is facilitated [49]. The higher level of fission in axons, compared to dendrites, explains why axonal mitochondria are typically observed as small and punctuate (up to 3 µm of length), while dendritic mitochondria are long and tubular (up to 36 µm of length) [45,50,51].…”

Section: Role Of Mitochondria In Neuronsmentioning

confidence: 99%

“…The higher level of fission in axons, compared to dendrites, explains why axonal mitochondria are typically observed as small and punctuate (up to 3 µm of length), while dendritic mitochondria are long and tubular (up to 36 µm of length) [45,50,51]. Altered mitochondrial fusion/fission dynamics has important consequences for mitochondria functionality and is implicated in many neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and ALS [49,52].…”

Section: Role Of Mitochondria In Neuronsmentioning

confidence: 99%

“…All together, these results suggest that mitochondria fragmentation is enhanced from early stage of development in all SMA types. Increased mitochondrial fragmentation may result from impaired fusion [77] or excessive fission [49,52], both implicated in the pathogenesis of many neurodegenerative diseases. Of note, decreased mitochondrial size and, importantly, decreased cristae density, may lead to low ATP synthesis efficiency [78].…”

Section: Mitochondrial Morphology Dynamics and Transport In Sma Neuronsmentioning

confidence: 99%

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Mitochondrial Dysfunction in Spinal Muscular Atrophy

Zilio

Piano

Wirth

2022

IJMS

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Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by recessive mutations in the SMN1 gene, globally affecting ~8–14 newborns per 100,000. The severity of the disease depends on the residual levels of functional survival of motor neuron protein, SMN. SMN is a ubiquitously expressed RNA binding protein involved in a plethora of cellular processes. In this review, we discuss the effects of SMN loss on mitochondrial functions in the neuronal and muscular systems that are the most affected in patients with spinal muscular atrophy. Our aim is to highlight how mitochondrial defects may contribute to disease progression and how restoring mitochondrial functionality may be a promising approach to develop new therapies. We also collected from previous studies a list of transcripts encoding mitochondrial proteins affected in various SMA models. Moreover, we speculate that in adulthood, when motor neurons require only very low SMN levels, the natural deterioration of mitochondria associated with aging may be a crucial triggering factor for adult spinal muscular atrophy, and this requires particular attention for therapeutic strategies.

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Section: Role Of Mitochondria In Neuronsmentioning

confidence: 99%

Section: Role Of Mitochondria In Neuronsmentioning

confidence: 99%

Section: Mitochondrial Morphology Dynamics and Transport In Sma Neuronsmentioning

confidence: 99%

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Mitochondrial Dysfunction in Spinal Muscular Atrophy

Zilio

Piano

Wirth

2022

IJMS

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Dynamins combine mechano-constriction and membrane remodeling to enable two-step mitochondrial fission via a ‘snap-through’ instability

Alimohamadi,

Luo,

Yang

et al. 2024

Preprint

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Mitochondrial fission is controlled by dynamin proteins, the dysregulation of which is correlated with diverse diseases. Fission dynamins are GTP hydrolysis-driven mechanoenzymes that self-oligomerize into helical structures that constrict membrane to achieve fission, but details are not well understood. However, dynamins can also remodel membranes by inducing negative Gaussian curvature, the type of curvature required for completion of fission. Here, we examine how these drastically different mechanisms synergistically exert their influences on a membrane, via a mechanical model calibrated with small-angle X-ray scattering structural data. We find that free dynamin can trigger a “snap-through instability” that enforces a shape transition from an oligomer-confined cylindrical membrane to a drastically narrower catenoid-shaped neck within the spontaneous hemi-fission regime, in a manner that depends critically on the length of the confined tube. These results indicate how the combination of dynamin assembly, and paradoxically disassembly, can lead to diverse pathways to scission.TeaserDynamin mechano-constriction by assembly and curvature-driven instability by free monomers synergistically drive mitochondrial fission.

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