Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics

Publication date: Available online 26 January 2017
Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Author(s): Gauri Bhosale, Jenny Sharpe, Amanda Koh, Antonina Kouli, Gyorgy Szabadkai, Michael R. Duchen
Loss of function mutations of the protein MICU1, a regulator of mitochondrial Ca²⁺ uptake, cause a neuronal and muscular disorder characterised by impaired cognition, muscle weakness and an extrapyramidal motor disorder. We have shown previously that MICU1 mutations cause increased resting mitochondrial Ca²⁺ concentration ([Ca²⁺]m). We now explore the functional consequences of MICU1 mutations in patient derived fibroblasts in order to clarify the underlying pathophysiology of this disorder. We propose that deregulation of mitochondrial Ca²⁺ uptake through loss of MICU1 raises resting [Ca²⁺]m, initiating a futile Ca²⁺ cycle, whereby continuous mitochondrial Ca²⁺ influx is balanced by Ca²⁺ efflux through the sodium calcium exchanger (NLCXm). Thus, inhibition of NLCXm by CGP37157 caused rapid mitochondrial Ca²⁺ accumulation in patient but not control cells. We suggest that increased NCX activity will increase sodium/proton exchange, potentially undermining oxidative phosphorylation, although this is balanced by dephosphorylation and activation of pyruvate dehydrogenase (PDH) in response to the increased [Ca²⁺]m. Consistent with this model, while ATP content in patient derived or control fibroblasts were not different, ATP increased significantly in response to CGP-37157 in the patient but not the control cells. The. In addition, EMRE expression levels are altered in MICU1 patient cells compared to the controls. The MICU1 mutations are associated with mitochondrial fragmentation which we show is related to altered DRP1 phosphorylation. Thus, MICU1 serves as a signal–noise discriminator in mitochondrial calcium signalling, limiting the energetic costs of mitochondrial Ca²⁺ signalling which may undermine oxidative phosphorylation, especially in tissues with highly dynamic energetic demands.



from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2k8uwtf
via IFTTT