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Kamer, Kimberli

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Kamer

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Kimberli

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Kamer, Kimberli
Author's Publications: search.filters.isAuthorOfPublication.43d35a85-fd28-40bb-ab74-1bca400bf87f

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    Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood
    (Wolters Kluwer, 2016) Lewis-Smith, David; Kamer, Kimberli; Griffin, Helen; Childs, Anne-Marie; Pysden, Karen; Titov, Denis; Duff, Jennifer; Pyle, Angela; Taylor, Robert W.; Yu-Wai-Man, Patrick; Ramesh, Venkateswaran; Horvath, Rita; Mootha, Vamsi; Chinnery, Patrick F.
    Objective: To define the mechanism responsible for fatigue, lethargy, and weakness in 2 cousins who had a normal muscle biopsy. Methods: Exome sequencing, long-range PCR, and Sanger sequencing to identify the pathogenic mutation. Functional analysis in the patient fibroblasts included oxygen consumption measurements, extracellular acidification studies, Western blotting, and calcium imaging, followed by overexpression of the wild-type protein. Results: Analysis of the exome sequencing depth revealed a homozygous deletion of exon 1 of MICU1 within a 2,755-base pair deletion. No MICU1 protein was detected in patient fibroblasts, which had impaired mitochondrial calcium uptake that was rescued through the overexpression of the wild-type allele. Conclusions: MICU1 mutations cause fatigue and lethargy in patients with normal mitochondrial enzyme activities in muscle. The fluctuating clinical course is likely mediated through the mitochondrial calcium uniporter, which is regulated by MICU1.
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    Cardiovascular homeostasis dependence on MICU2, a regulatory subunit of the mitochondrial calcium uniporter
    (National Academy of Sciences, 2017) Bick, Alexander; Wakimoto, Hiroko; Kamer, Kimberli; Sancak, Yasemin; Goldberger, Olga; Axelsson, Anna; DeLaughter, Daniel; Gorham, Joshua; Mootha, Vamsi; Seidman, J. G.; Seidman, Christine
    Comparative analyses of transcriptional profiles from humans and mice with cardiovascular pathologies revealed consistently elevated expression of MICU2, a regulatory subunit of the mitochondrial calcium uniporter complex. To determine if MICU2 expression was cardioprotective, we produced and characterized Micu2−/− mice. Mutant mice had left atrial enlargement and Micu2−/− cardiomyocytes had delayed sarcomere relaxation and cytosolic calcium reuptake kinetics, indicating diastolic dysfunction. RNA sequencing (RNA-seq) of Micu2−/− ventricular tissues revealed markedly reduced transcripts encoding the apelin receptor (Micu2−/− vs. wild type, P = 7.8 × 10−40), which suppresses angiotensin II receptor signaling via allosteric transinhibition. We found that Micu2−/− and wild-type mice had comparable basal blood pressures and elevated responses to angiotensin II infusion, but that Micu2−/− mice exhibited systolic dysfunction and 30% lethality from abdominal aortic rupture. Aneurysms and rupture did not occur with norepinephrine-induced hypertension. Aortic tissue from Micu2−/− mice had increased expression of extracellular matrix remodeling genes, while single-cell RNA-seq analyses showed increased expression of genes related to reactive oxygen species, inflammation, and proliferation in fibroblast and smooth muscle cells. We concluded that Micu2−/− mice recapitulate features of diastolic heart disease and define previously unappreciated roles for Micu2 in regulating angiotensin II-mediated hypertensive responses that are critical in protecting the abdominal aorta from injury.
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    MICU2, a Paralog of MICU1, Resides within the Mitochondrial Uniporter Complex to Regulate Calcium Handling
    (Public Library of Science, 2013) Plovanich, Molly; Bogorad, Roman L.; Sancak, Yasemin; Kamer, Kimberli; Strittmatter, Laura Anne; Li, Andrew A.; Girgis, Hany S.; Kuchimanchi, Satya; De Groot, Jack; Speciner, Lauren; Taneja, Nathan; OShea, Jonathan; Koteliansky, Victor; Mootha, Vamsi
    Mitochondrial calcium uptake is present in nearly all vertebrate tissues and is believed to be critical in shaping calcium signaling, regulating ATP synthesis and controlling cell death. Calcium uptake occurs through a channel called the uniporter that resides in the inner mitochondrial membrane. Recently, we used comparative genomics to identify MICU1 and MCU as the key regulatory and putative pore-forming subunits of this channel, respectively. Using bioinformatics, we now report that the human genome encodes two additional paralogs of MICU1, which we call MICU2 and MICU3, each of which likely arose by gene duplication and exhibits distinct patterns of organ expression. We demonstrate that MICU1 and MICU2 are expressed in HeLa and HEK293T cells, and provide multiple lines of biochemical evidence that MCU, MICU1 and MICU2 reside within a complex and cross-stabilize each other's protein expression in a cell-type dependent manner. Using in vivo RNAi technology to silence MICU1, MICU2 or both proteins in mouse liver, we observe an additive impairment in calcium handling without adversely impacting mitochondrial respiration or membrane potential. The results identify MICU2 as a new component of the uniporter complex that may contribute to the tissue-specific regulation of this channel.