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Although the role of the protein is well understood, the precise molecular pathophysiology leading to this neuropaediatric phenotype has not been fully elucidated. Here we aimed to obtain novel insights into MICU1 pathophysiology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Molecular genetic studies along with proteomic profiling, electron\u2010, light\u2010 and Coherent anti\u2010Stokes Raman scattering microscopy and immuno\u2010based studies of protein abundances and Ca<jats:sup>2+<\/jats:sup> transport studies were employed to examine the pathophysiology of MICU1 deficiency in humans.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We describe two patients carrying <jats:italic>MICU1<\/jats:italic> mutations, two nonsense (c.52C&gt;T; p.(Arg18*) and c.553C&gt;T; p.(Arg185*)) and an intragenic exon 2\u2010deletion presenting with ataxia, developmental delay and early onset myopathy, clinodactyly, attention deficits, insomnia and impaired cognitive pain perception. Muscle biopsies revealed signs of dystrophy and neurogenic atrophy, severe mitochondrial perturbations, altered Golgi structure, vacuoles and altered lipid homeostasis. Comparative mitochondrial Ca<jats:sup>2+<\/jats:sup> transport and proteomic studies on lymphoblastoid cells revealed that the [Ca<jats:sup>2+<\/jats:sup>] threshold and the cooperative activation of mitochondrial Ca<jats:sup>2+<\/jats:sup> uptake were lost in MICU1\u2010deficient cells and that 39 proteins were altered in abundance. Several of those proteins are linked to mitochondrial dysfunction and\/or perturbed Ca<jats:sup>2+<\/jats:sup> homeostasis, also impacting on regular cytoskeleton (affecting Spectrin) and Golgi architecture, as well as cellular survival mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings (i) link dysregulation of mitochondrial Ca<jats:sup>2+<\/jats:sup> uptake with muscle pathology (including perturbed lipid homeostasis and ER\u2013Golgi morphology), (ii) support the concept of a functional interplay of ER\u2013Golgi and mitochondria in lipid homeostasis and (iii) reveal the vulnerability of the cellular proteome as part of the MICU1\u2010related pathophysiology.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12694","type":"journal-article","created":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T05:56:25Z","timestamp":1610690185000},"page":"840-855","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Molecular pathophysiology of human MICU1 deficiency"],"prefix":"10.1111","volume":"47","author":[{"given":"Nicolai","family":"Kohlschmidt","sequence":"first","affiliation":[{"name":"Institute of Clinical Genetics and Tumour Genetics  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Elbracht","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics RWTH Aachen University Hospital  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur","family":"Czech","sequence":"additional","affiliation":[{"name":"Leibniz\u2010Institut f\u00fcr Analytische Wissenschaften \u2010 ISAS 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