Wolfram syndrome: MAMs’ connection?

Abstract

Wolfram syndrome (WS) is a rare neurodegenerative disease, the main pathological hallmarks of which associate with diabetes, optic atrophy, and deafness. Other symptoms may be identified in some but not all patients. Prognosis is poor, with death occurring around 35 years of age. To date, no treatment is available. WS was first described as a mitochondriopathy. However, the localization of the protein on the endoplasmic reticulum (ER) membrane challenged this hypothesis. ER contacts mitochondria to ensure effective Ca2+ transfer, lipids transfer, and apoptosis within stabilized and functionalized microdomains, termed “mitochondria-associated ER membranes” (MAMs). Two types of WS are characterized so far and Wolfram syndrome type 2 is due to mutation in CISD2, a protein mostly expressed in MAMs. The aim of the present review is to collect evidences showing that WS is indeed a mitochondriopathy, with established MAM dysfunction, and thus share commonalities with several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, as well as metabolic diseases, such as diabetes.

Contact-ID, a tool for profiling organelle contact sites, reveals regulatory proteins of mitochondrial-associated membrane formation

“…S9). We also expect that our Contact-ID method can resolve the proteomic architecture of an abnormally increased MAM in type 2 diabetes (81), obesity (34), and neurodegenerative diseases (10,13,14,82).…”

“…For example, the mitochondrial-associated membrane (MAM) of the endoplasmic reticulum (ER) is reported to regulate many physiological processes such as calcium homeostasis (4), lipid transport (5), organelle biogenesis (6), organelle stress regulation (7)(8)(9), and cell cycle regulation (10,11). Additionally, the MAM is closely related to a wide spectrum of metabolic diseases, such as type 2 diabetes (12) and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (13), and Wolfram syndrome (14). This accumulating evidence suggests that MAM functions as a molecular sensory hub and conducts cellular signaling in a variety of physiological and pathological processes, including viral infection, pharmacological stresses, and aging (8,9,(15)(16)(17).…”

Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome

“…Further studies are warranted to mechanistically define the ER-mitochondrial calcium handling in the pathogenesis of WS. Calcium mishandling and ER-stress may have far reaching consequences in the context of neuronal cells 19 , representing a druggable target for therapeutic strategies in WS patients, as suggested by WFS1 knock-out cell models 47,52 .…”

“…However, recent reports resumed the debate documenting in Wfs1−/− mice disturbed mitochondrial network dynamics and activation of mitophagy 13 . Noticeably, recessive mutations in CDGSH Iron Sulfur Domain 2 (CISD2) gene, encoding a protein localized in the mitochondria-associated ER membranes (MAMs), are causative for Wolfram syndrome type 2 [14][15][16][17][18][19] . As shown for Wfs1, also Cisd2 knock out mouse model and mouse embryonic fibroblast (MEF) studies documented mitochondrial dysfunction as evidenced by ultrastructural alterations of mitochondria, increased oxygen consumption and ADP/ATP ratio, and overload of mitochondrial calcium (Ca 2+ ) 20,21 .…”

MERCs. The Novel Assistant to Neurotransmission?

“…Taking into account the number of cellular functions carried out with MERCs, it appears to be natural that mutant forms or altered functions of several resident proteins are implicated in the course of neurological pathologies (Veeresh et al, 2019). Such pathologies include proteinopathies (Poston et al, 2013;Paillusson et al, 2016) and metabolic disorders in Wolfram syndrome (Wiley et al, 2013;Delprat et al, 2018) and GM1-gangliosidosis (Sano et al, 2009). Abnormalities in the structure of the genes encoding MERCs-localized functional protein complexes appear to be an important part of neurodegeneration.…”