Mitochondria affected in SPG11

Altered structure, function and transport found

Alterations in structure, function and transport of mitochondria are an important feature of axonal dysfunction in SPG11 motor neurons.

Mitochondria are organelles, several thousand of which are in nearly every cell in the body. They are ‘energy factories’, producing most of the energy the body needs to function.


Pathogenic variants in SPG11 are the most frequent cause of autosomal recessive complicated hereditary spastic paraplegia (HSP). In addition to spastic paraplegia caused by corticospinal degeneration, most patients are significantly affected by progressive weakness and muscle wasting due to alpha motor neuron (MN) degeneration. Mitochondria play a crucial role in neuronal health, and mitochondrial deficits were reported in other types of HSPs.

To investigate whether mitochondrial pathology is present in SPG11, we differentiated MNs from induced pluripotent stem cells derived from SPG11 patients and controls. MN derived from human embryonic stem cells and an isogenic SPG11 knockout line were also included in the study. Morphological analysis of mitochondria in the MN soma versus neurites revealed specific alterations of mitochondrial morphology within SPG11 neurites, but not within the soma. In addition, impaired mitochondrial membrane potential was indicative of mitochondrial dysfunction. Moreover, we reveal neuritic aggregates further supporting neurite pathology in SPG11. Correspondingly, using a microfluidic-based MN culture system, we demonstrate that axonal mitochondrial transport was significantly impaired in SPG11.

Overall, our data demonstrate that alterations in morphology, function, and transport of mitochondria are an important feature of axonal dysfunction in SPG11 MNs.

SOURCE:  Front Neurosci. 2021 Jul 7;15:680572. doi: 10.3389/fnins.2021.680572. eCollection 2021. PMID: 34326717 Copyright © 2021 Güner, Pozner, Krach, Prots, Loskarn, Schlötzer-Schrehardt, Winkler, Winner and Regensburger.

Axon-Specific Mitochondrial Pathology in SPG11 Alpha Motor Neurons

Fabian Güner  1 Tatyana Pozner  1 Florian Krach  1 Iryna Prots  1 Sandra Loskarn  1 Ursula Schlötzer-Schrehardt  2 Jürgen Winkler  3   4 Beate Winner  1   4 Martin Regensburger  1   3   4

1. Department of Stem Cell Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

2. Department of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

3. Department of Molecular Neurology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

4. Center for Rare Diseases Erlangen, University Hospital Erlangen, Erlangen, Germany.

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