ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.

Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca handling compromises mitochondrial function and affects neuronal health.

PMPCA-Related Encephalopathy: Novel Variants, Phenotype Extension, and Mitochondrial Morphology.

Objectives: The gene encodes the α-subunit of mitochondrial processing peptidase (α-MPP), an enzyme responsible for cleavage of nuclear-encoded mitochondrial precursor proteins after their import into mitochondria. Mutations in this gene have been described in patients with nonprogressive or slow progressive cerebellar ataxia, with variable age at onset and severity. Cerebellar atrophy and striatum changes were found in severe cases.

Time-Resolved Imaging of Mitochondrial Flavin Fluorescence and Its Applications for Evaluating the Oxidative State in Living Cardiac Cells.

Time-resolved fluorescence spectrometry is a highly valuable technological tool to detect and characterize mitochondrial metabolic oxidative changes by means of endogenous fluorescence. Here, we describe detection and measurement of endogenous mitochondrial flavin fluorescence directly in living cardiac cells using fluorescence lifetime imaging microscopy (FLIM) after excitation with 473 nm picoseconds (ps) laser. Time-correlated single photon counting (TCSPC) method is employed.

Lack of functional wolframin causes drop in plasmalemmal sodium-calcium exchanger type 1 expression at early stage in rat model of Wolfram syndrome.

In previously introduced rat model of Wolfram syndrome, we have shown that in cardiac myocytes lacking functional wolframin protein the calcium transients and contractile response are significantly changed. Therefore, in this model, we evaluated protein and mRNA expression levels of following proteins involved in cardiac myocytes calcium homeostasis: the ryanodine receptor type 2, calsequestrin type 2, the junctophilin type 2 and plasmalemmal sodium-calcium exchanger type 1 (NCX1). For NCX1 we detected a significant decrease in expression both on protein and mRNA level.

L-type Ca channel-mediated Ca influx adjusts neuronal mitochondrial function to physiological and pathophysiological conditions.

L-type voltage-gated Ca channels (LTCCs) are implicated in neurodegenerative processes and cell death. Accordingly, LTCC antagonists have been proposed to be neuroprotective, although this view is disputed, because intentional LTCC activation can also have beneficial effects. LTCC-mediated Ca influx influences mitochondrial function, which plays a crucial role in the regulation of cell viability.