Altered interplay between endoplasmic reticulum and mitochondria in Charcot-Marie-Tooth type 2A neuropathy

Mutations in the MFN2 gene encoding Mitofusin 2 lead to the development of Charcot-Marie-Tooth type 2A (CMT2A), a dominant axonal form of peripheral neuropathy. Mitofusin 2 is localized at both the outer membrane of mitochondria and the endoplasmic reticulum and is particularly enriched at specialized contact regions known as mitochondria-associated membranes (MAM). We observed that expression of MFN2R94Q induces distal axonal degeneration in the absence of overt neuronal death. The presence of mutant protein leads to reduction in endoplasmic reticulum and mitochondria contacts in CMT2A patient-derived fibroblasts, in primary neurons and in vivo, in motoneurons of a mouse model of CMT2A. These changes are concomitant with endoplasmic reticulum stress, calcium handling defects, and changes in the geometry and axonal transport of mitochondria. Importantly, pharmacological treatments reinforcing endoplasmic reticulum-mitochondria cross-talk, or reducing endoplasmic reticulum stress, restore the mitochondria morphology and prevent axonal degeneration. These results highlight defects in MAM as a cellular mechanism contributing to CMT2A pathology mediated by mutated MFN2.

Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration

Nathalie Marie Géraldine Bernard, Roman Chrast

Mutations in SIGMAR1, which encodes the Sigma 1 receptor, cause a familial form of amyotrophic lateral sclerosis, but the underlying molecular mechanisms are unclear. Bernard-Marissal et al. reveal that disruption of Sigma 1 receptor function disturbs endoplasmic reticulum-mitochondria interactions and functions, resulting in degeneration specifically of motor neurons.Mutations in Sigma 1 receptor (SIGMAR1) have been previously identified in patients with amyotrophic lateral sclerosis and disruption of Sigmar1 in mouse leads to locomotor deficits. However, cellular mechanisms underlying motor phenotypes in human and mouse with disturbed SIGMAR1 function have not been described so far. Here we used a combination of in vivo and in vitro approaches to investigate the role of SIGMAR1 in motor neuron biology. Characterization of Sigmar1(-/-) mice revealed that affected animals display locomotor deficits associated with muscle weakness, axonal degeneration and motor neuron loss. Using primary motor neuron cultures, we observed that pharmacological or genetic inactivation of SIGMAR1 led to motor neuron axonal degeneration followed by cell death. Disruption of SIGMAR1 function in motor neurons disturbed endoplasmic reticulum-mitochondria contacts, affected intracellular calcium signalling and was accompanied by activation of endoplasmic reticulum stress and defects in mitochondrial dynamics and transport. These defects were not observed in cultured sensory neurons, highlighting the exacerbated sensitivity of motor neurons to SIGMAR1 function. Interestingly, the inhibition of mitochondrial fission was sufficient to induce mitochondria axonal transport defects as well as axonal degeneration similar to the changes observed after SIGMAR1 inactivation or loss. Intracellular calcium scavenging and endoplasmic reticulum stress inhibition were able to restore mitochondrial function and consequently prevent motor neuron degeneration. These results uncover the cellular mechanisms underlying motor neuron degeneration mediated by loss of SIGMAR1 function and provide therapeutically relevant insight into motor neuronal diseases.

Oxford University Press2015

The effect of the functional interaction between PGC-1α and Parkin on mitochondrial quality control in Parkinson's disease

Lu Zheng

Although several genetic factors have been directly associated to Parkinsonâs disease (PD), no single pathway has emerged to explain the etiology of this neurodegenerative disease. To further understand the cause of Parkinsonâs disease (PD), it is therefore important to deter-mine if and which functional interactions exist between gene products linked to this complex brain disorder. Mutations in the gene encoding the E3 ubiquitin ligase Parkin are associated to autosomal recessive PD with early onset. Although the Parkin protein carries out various critical func-tions in the cell, its role in mitochondria quality control, by inducing the autophagic degrada-tion of damaged mitochondria, has attracted a lot of attention. Furthermore, Parkin has been found to control the transcription of PGC-1Î±, a master regulator of mitochondrial biogenesis. Based on the important role that mitochondria are considered to play in PD, and the evi-dence for the coordinated expression of Parkin and PGC-1Î±, we sought to explore in neurons how these two factors functionally interact to regulate mitochondria turnover and quality control. In cortical neuronal cultures, we found that Parkin and PGC-1Î± have synergistic effects on mitochondrial biogenesis, and that the co-expression of these two factors leads to a dramatic increase in the number of mitochondria per cell. We further explored the effects of these fac-tors on the mitochondrial function. Parkin was shown to enhance the maximal respiration rate of neurons exposed to a mitochondrial uncoupling agent only in the presence of PGC-1Î±. Consistent with this effect, the co-expression of Parkin and PGC-1Î± leads to rapid recovery of the mitochondrial membrane potential following mitochondrial uncoupling. Next, we explored the molecular changes, which may underlie the cooperation between Par-kin and PGC-1Î±. The expression of Tfam, an important mitochondrial transcription factor, was found to be controlled synergistically by these two factors. Furthermore, PGC-1Î± en-hances the turnover of Mfn2, a key ubiquitylation target of Parkin. This result suggests that part of the functional interaction between PGC-1Î± and Parkin may be mediated via the co-regulation of Mfn2, a critical factor in mitochondrial physiology which controls the dynamics of mitochondria as well as their association with the endoplasmic reticulum (ER). In the rat substantia nigra, Parkin activity has significant protective effects on the survival and function of nigral dopaminergic neurons in which the chronic expression of PGC-1Î± is in-duced. Ultrastructural analysis shows that the conjunction of these two factors controls the density of mitochondria and their interaction with the ER. In PGC-1Î±-expressing dopamin-ergic neurons, the co-expression of mutated variants of Parkin associated with familial PD leads to accelerated degeneration. Overall, this study shows that Parkin, in conjunction with the transcription co-regulator PGC-1Î±, may play an important role in modulating the biogenesis of mitochondria as well as the quality control of this organelle. In nigral dopaminergic neurons which may critically depend on the mitochondria for their function and survival, the functional interaction be-tween these two factors should be further explored in the context of PD.

EPFL2016

The effect of the functional interaction between PGC-1α and Parkin on mitochondrial quality control in Parkinson's disease

Lu Zheng

EPFL2016

Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration

Nathalie Marie Géraldine Bernard, Roman Chrast

Oxford University Press2015