bims-cytox1 2019-06-16 papers

Issue of 2019‒06‒16
four papers selected by
Gavin McStay
Staffordshire University

Biochim Biophys Acta Mol Cell Res. 2019 Jun 10. pii: S0167-4889(19)30097-7. [Epub ahead of print]

The MELAS mutation m.3243A>G alters the expression of mitochondrial tRNA fragments.

Salvador Meseguer, Carmen Navarro-González, Joaquin Panadero, Magda Villarroya, Rachid Boutoual, Jose Antonio Sánchez-Alcázar, M-Eugenia Armengod.

Recent evidences highlight the importance of mitochondria-nucleus communication for the clinical phenotype of oxidative phosphorylation (OXPHOS) diseases. However, the participation of small non-coding RNAs (sncRNAs) in this communication has been poorly explored. We asked whether OXPHOS dysfunction alters the production of a new class of sncRNAs, mitochondrial tRNA fragments (mt tRFs), and, if so, whether mt tRFs play a physiological role and their accumulation is controlled by the action of mt tRNA modification enzymes. To address these questions, we used a cybrid model of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), an OXPHOS disease mostly caused by mutation m.3243A>G in the mitochondrial tRNALeu(UUR) gene. High-throughput analysis of small-RNA-Seq data indicated that m.3243A>G significantly changed the expression pattern of mt tRFs. A functional analysis of potential mt tRFs targets (performed under the assumption that these tRFs act as miRNAs) indicated an association with processes that involve the most common affected tissues in MELAS. We present evidences that mt tRFs may be biologically relevant, as one of them (mt i-tRF GluUUC), likely produced by the action of the nuclease Dicer and whose levels are Ago2 dependent, down-regulates the expression of mitochondrial pyruvate carrier 1 (MPC1), promoting the build-up of extracellular lactate. Therefore, our study underpins the idea that retrograde signaling from mitochondria is also mediated by mt tRFs. Finally, we show that accumulation of mt i-tRF GluUUC depends on the modification status of mt tRNAs, which is regulated by the action of stress-responsive miRNAs on mt tRNA modification enzymes.

Keywords: GTPBP3/MTO1/TRMU; Mitochondrial dysfunction; Mitochondrial-tRNA modification; Retrograde signaling; miRNAs; sncRNAs

DOI: https://doi.org/10.1016/j.bbamcr.2019.06.004

Mitochondrion. 2019 Jun 10. pii: S1567-7249(19)30086-8. [Epub ahead of print]

Consequences of inner mitochondrial membrane protein misfolding.

Liam P Coyne, Xin Jie Chen.

Proteins embedded in the inner mitochondrial membrane (IMM) perform essential cellular functions. Maintaining the folding state of these proteins is therefore of the utmost importance, and this is ensured by IMM chaperones and proteases that refold and degrade unassembled and misfolded proteins. However, the physiological consequences specific to IMM protein misfolding remain obscure because deletion of these chaperones/proteases (the typical experimental strategy) often affects many mitochondrial processes other than protein folding and turnover. Thus, novel experimental systems are needed to evaluate the direct effects of misfolded protein on the membrane. Such a system has been developed in recent years. Studies suggest that numerous pathogenic mutations in isoform 1 of adenine nucleotide translocase (Ant1) cause its misfolding on the IMM. In this review, we first discuss potential mechanisms by which dominant Ant1 mutations may cause disease, highlighting IMM protein misfolding, per se, as a likely pathological factor. Then we discuss the intramitochondrial effects of Ant1 misfolding such as IMM proteostatic stress, respiratory chain dysfunction, and mtDNA instability. Finally, we summarize the mounting evidence that IMM proteostatic stress can perturb mitochondrial protein import to cause the toxic accumulation of mitochondrial proteins in the cytosol: a cell stress mechanism termed mitochondrial Precursor Overaccumulation Stress (mPOS).

Keywords: Ant1; Misfolding; Mitochondria; Mitochondrial carrier; mPOS

DOI: https://doi.org/10.1016/j.mito.2019.06.001

Brain Dev. 2019 Jun 06. pii: S0387-7604(19)30117-2. [Epub ahead of print]

Transition from Leigh syndrome to MELAS syndrome in a patient with heteroplasmic MT-ND3 m.10158T>C.

Atsuko Kori, Ikumi Hori, Tatsushi Tanaka, Kohei Aoyama, Koichi Ito, Ayako Hattori, Kyoko Ban, Yasushi Okazaki, Kei Murayama, Shinji Saitoh.

An m.10158T>C mutation in MT-ND3, encoding a subunit of respiratory complex I, causes early-onset Leigh syndrome (LS), mitochondrial encephalomyopathy with lactic acid and stroke-like episodes (MELAS) syndrome, and LS and MELAS overlapping syndrome, presumably dependent on the ratio of heteroplasmy. Herein, we report a 4-year-old girl with heteroplasmic m.10158T>C mutation, showing an evolving age-dependent phenotype from LS to MELAS syndromes. She showed mild developmental delay during infancy, which was associated with magnetic resonance imaging lesions in the brain stem and basal ganglia. At the age of 4 years, she developed rapid neurological deterioration and intractable seizures, which was associated with recurrent multiple cerebral lesions as well as basal ganglia lesions. Her cerebral lesions were located predominantly in white matter and appeared at multiple areas simultaneously, unique characteristics that are distinct from typical MELAS. Two patients with LS-MELAS overlapping syndrome with m.10158T>C have been previously reported, however, this is the first patient with m.10158T>C showing significant age-dependent changes in clinical features and neuro-images, implying an age-dependent role of complex I in the developing brain.

Keywords: Mitochondrial disease; Neuroimaging; Respiratory complex I

DOI: https://doi.org/10.1016/j.braindev.2019.05.006

Antimicrob Agents Chemother. 2019 Jun 10. pii: AAC.00374-19. [Epub ahead of print]

The novel arylamidine T-2307 selectively disrupts yeast mitochondrial function by inhibiting respiratory chain complexes.

Kohei Yamashita, Taiga Miyazaki, Yoshiko Fukuda, Junichi Mitsuyama, Tomomi Saijo, Shintaro Shimamura, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae.

The novel arylamidine T-2307 exhibits broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens. Previous studies have shown that T-2307 accumulates in yeast cells via a specific polyamine transporter and disrupts yeast mitochondrial membrane potential. Further, it has little effect on rat liver mitochondrial function. The mechanism by which T-2307 disrupts yeast mitochondrial function is poorly understood, and its elucidation may provide important information for developing novel antifungal agents. This study aimed to understand how T-2307 promotes yeast mitochondrial dysfunction and to investigate the selectivity of this mechanism between fungi and mammals. T-2307 inhibited the respiration of yeast whole cells and isolated yeast mitochondria in a dose-dependent manner. The similarity of the effects of T-2307 and respiratory chain inhibitors on mitochondrial respiration prompted us to investigate the effect of T-2307 on mitochondrial respiratory chain complexes. T-2307 particularly inhibited respiratory chain complexes III and IV not only in Saccharomyces cerevisiae but also in Candida albicans, indicating that T-2307 acts against pathogenic fungi in a manner similar to that of yeast. Conversely, T-2307 showed little effect on bovine respiratory chain complexes. Additionally, we demonstrated that the inhibition of respiratory chain complexes by T-2307 resulted in a decrease in the intracellular ATP levels in yeast cells. These results indicate that the inhibition of respiratory chain complexes III and IV is a key for selective disruption of yeast mitochondrial function and antifungal activity.

DOI: https://doi.org/10.1128/AAC.00374-19