Charcot–Marie–Tooth disease (CMT) type 2A is a form of peripheral neuropathy, due almost exclusively to dominant mutations in the nuclear gene encoding the mitochondrial protein mitofusin-2 ( MFN2 ). However, there is no understanding of the relationship of clinical phenotype to genotype. MFN2 has two functions: it promotes inter-mitochondrial fusion and mediates endoplasmic reticulum (ER)–mitochondrial tethering at mitochondria-associated ER membranes (MAM). MAM regulates a number of key cellular functions, including lipid and calcium homeostasis, and mitochondrial behavior. To date, no studies have been performed to address whether mutations in MFN2 in CMT2A patient cells affect MAM function, which might provide insight into pathogenesis. Using fibroblasts from three CMT2A MFN2 patients with different mutations in MFN2 , we found that some, but not all, examined aspects of ER–mitochondrial connectivity and of MAM function were indeed altered, and correlated with disease severity. Notably, however, respiratory chain function in those cells was unimpaired. Our results suggest that CMT2A MFN2 is a MAM-related disorder but is not a respiratory chain-deficiency disease. The alterations in MAM function described here could also provide insight into the pathogenesis of other forms of CMT.

The occurrence of suitable mycorrhizal inocula may be an important factor affecting the dynamics of plant communities. We investigated the persistence and diversity of ericoid mycorrhizal fungi in the soil of a mature Quercus ilex forest where ericaceous hosts were absent. Erica arborea was used as a bait plant and results were compared to soil samples from experimental plots where cuttings had allowed reappearance of this ericaceous species. Fungal endophytes were isolated and tested in mycorrhiza resynthesis trials. Sterile mycorrhizal endophytes were assigned to morphotypes whose consistency was confirmed by ITS-RFLP. The ITS region of a representative of each morphotype was sequenced. BLAST searches and Neighbour-Joining analysis indicated taxonomic affinities with different classes within Ascomycota. Our results indicate that ericoid mycorrhizal fungi persist and maintain mycorrhizal ability in habitats lacking the ericaceous host. Their persistence could favour the establishment of E. arborea seedlings in pure Q. ilex forests after disturbance phenomena.

Contact sites between mitochondria and endoplasmic reticulum (ER) are points in which the two organelles are in close proximity. Due to their structural and functional complexity, their exploitation as pharmacological targets has never been considered so far. Notwithstanding, the number of compounds described to target proteins residing at these interfaces either directly or indirectly is rising. Here we provide original insight into mitochondria–ER contact sites (MERCs), with a comprehensive overview of the current MERCs pharmacology. Importantly, we discuss the considerable potential of MERCs to become a druggable target for the development of novel therapeutic strategies.

Charcot-Marie-Tooth (CMT) disease 4A is an autosomal-recessive polyneuropathy caused by mutations of ganglioside-induced differentiation-associated protein 1 (GDAP1), a putative glutathione transferase, which affects mitochondrial shape and alters cellular Ca2+ homeostasis. Here, we identify the underlying mechanism. We found that patient-derived motoneurons and GDAP1 knockdown SH-SY5Y cells display two phenotypes: more tubular mitochondria and a metabolism characterized by glutamine dependence and fewer cytosolic lipid droplets. GDAP1 interacts with the actin-depolymerizing protein Cofilin-1 and beta-tubulin in a redox-dependent manner, suggesting a role for actin signaling. Consistently, GDAP1 loss causes less F-actin close to mitochondria, which restricts mitochondrial localization of the fission factor dynamin-related protein 1, instigating tubularity. GDAP1 silencing also disrupts mitochondria-ER contact sites. These changes result in lower mitochondrial Ca2+ levels and inhibition of the pyruvate dehydrogenase complex, explaining the metabolic changes upon GDAP1 loss of function. Together, our findings reconcile GDAP1-associated phenotypes and implicate disrupted actin signaling in CMT4A pathophysiology.