bims-cytox1 2018-01-07 papers

Dev Cell. 2017 Dec 26. pii: S1534-5807(17)30984-X. [Epub ahead of print]

Lipid Homeostasis Is Maintained by Dual Targeting of the Mitochondrial PE Biosynthesis Enzyme to the ER.

Jonathan R Friedman, Muthukumar Kannan, Alexandre Toulmay, Calvin H Jan, Jonathan S Weissman, William A Prinz, Jodi Nunnari.

Spatial organization of phospholipid synthesis in eukaryotes is critical for cellular homeostasis. The synthesis of phosphatidylcholine (PC), the most abundant cellular phospholipid, occurs redundantly via the ER-localized Kennedy pathway and a pathway that traverses the ER and mitochondria via membrane contact sites. The basis of the ER-mitochondrial PC synthesis pathway is the exclusive mitochondrial localization of a key pathway enzyme, phosphatidylserine decarboxylase Psd1, which generates phosphatidylethanolamine (PE). We find that Psd1 is localized to both mitochondria and the ER. Our data indicate that Psd1-dependent PE made at mitochondria and the ER has separable cellular functions. In addition, the relative organellar localization of Psd1 is dynamically modulated based on metabolic needs. These data reveal a critical role for ER-localized Psd1 in cellular phospholipid homeostasis, question the significance of an ER-mitochondrial PC synthesis pathway to cellular phospholipid homeostasis, and establish the importance of fine spatial regulation of lipid biosynthesis for cellular functions.

Keywords: ER; ER-mitochondria contacts; lipid transport; mitochondria; phosphatidylserine decarboxylase; phospholipid biosynthesis

DOI: https://doi.org/10.1016/j.devcel.2017.11.023

Biol Psychiatry. 2017 Nov 20. pii: S0006-3223(17)32209-6. [Epub ahead of print]

Mitochondrial Etiology of Neuropsychiatric Disorders.

Liming Pei, Douglas C Wallace.

The brain has the highest mitochondrial energy demand of any organ. Therefore, subtle changes in mitochondrial energy production will preferentially affect the brain. Considerable biochemical evidence has accumulated revealing mitochondrial defects associated with neuropsychiatric diseases. Moreover, the mitochondrial genome encompasses over a thousand nuclear DNA genes plus hundreds to thousands of copies of the maternally inherited mitochondrial DNA (mtDNA). Therefore, partial defects in either the nuclear DNA or mtDNA genes or combinations of the two can be sufficient to cause neuropsychiatric disorders. Inherited and acquired mtDNA mutations have recently been associated with autism spectrum disorder, which parallels previous evidence of mtDNA variation in other neurological diseases. Therefore, mitochondrial dysfunction may be central to the etiology of a wide spectrum of neurological diseases. The mitochondria and the nucleus communicate to coordinate energy production and utilization, providing the potential for therapeutics by manipulating nuclear regulation of mitochondrial gene expression.

Keywords: Alzheimer's disease; Autism; Mitochondria; OXPHOS; mtDNA; nuclear receptors

DOI: https://doi.org/10.1016/j.biopsych.2017.11.018

Stem Cell Res. 2017 Dec 19. pii: S1873-5061(17)30272-6. [Epub ahead of print]27 10-14

Generation of an induced pluripotent stem cell (iPSC) line from a 40-year-old patient with the A8344G mutation of mitochondrial DNA and MERRF (myoclonic epilepsy with ragged red fibers) syndrome.

Yu-Ting Wu, Yu-Hung Hsu, Ching-Ying Huang, Ming-Ching Ho, Yu-Che Cheng, Cheng-Hao Wen, Hui-Wen Ko, Huai-En Lu, Yen-Chun Chen, Chia-Ling Tsai, Yi-Chao Hsu, Yau-Huei Wei, Patrick C H Hsieh.

Mitochondrial defects are associated with clinical manifestations from common diseases to rare genetic disorders. Myoclonus epilepsy associated with ragged-red fibers (MERRF) syndrome results from an A to G transition at nucleotide position 8344 in the tRNALys gene of mitochondrial DNA (mtDNA) and is characterized by myoclonus, myopathy and severe neurological symptoms. In this study, Sendai reprogramming method was used to generate an iPS cell line carrying the A8344G mutation of mtDNA from a MERRF patient. This patient-specific iPSC line expressed pluripotent stem cell markers, possessed normal karyotype, and displayed the capability to differentiate into mature cells in three germ layers.

DOI: https://doi.org/10.1016/j.scr.2017.12.013

Mitochondrion. 2017 Dec 28. pii: S1567-7249(17)30162-9. [Epub ahead of print]

Cognitive impairment, clinical severity and MRI changes in MELAS syndrome.

Torsten Kraya, Lena Neumann, Yvonne Paelecke-Habermann, Marcus Deschauer, Dietrich Stoevesandt, Stephan Zierz, Stefan Watzke.

OBJECTIVE: To examine clinical severity, cognitive impairment, and MRI changes in patients with MELAS syndrome.
METHODS: Cognitive-mnestic functions, brain MRI (lesion load, cella media index) and clinical severity of ten patients with MELAS syndrome were examined. All patients carried the m.3243A>G mutation.
RESULTS: The detailed neuropsychological assessment revealed cognitive deficits in attention, executive function, visuoperception, and -construction. There were significant correlations between these cognitive changes, lesion load in MRI, disturbances in everyday life (clinical scale), and high scores in NMDAS.
CONCLUSION: Patients with MELAS syndrome showed no global neuropsychological deficit, but rather distinct cognitive deficits.

Keywords: Cognitive impairment; Dementia; MELAS; MRI; Mitochondrial disorders

DOI: https://doi.org/10.1016/j.mito.2017.12.012