bims-cytox1 2017-02-19 papers

J Cell Biol. 2017 Feb 10. pii: jcb.201607019. [Epub ahead of print]

CLUH regulates mitochondrial metabolism by controlling translation and decay of target mRNAs.

Désirée Schatton, David Pla-Martin, Marie-Charlotte Marx, Henriette Hansen, Arnaud Mourier, Ivan Nemazanyy, Alberto Pessia, Peter Zentis, Teresa Corona, Vangelis Kondylis, Esther Barth, Astrid C Schauss, Vidya Velagapudi, Elena I Rugarli.

Mitochondria are essential organelles that host crucial metabolic pathways and produce adenosine triphosphate. The mitochondrial proteome is heterogeneous among tissues and can dynamically change in response to different metabolic conditions. Although the transcriptional programs that govern mitochondrial biogenesis and respiratory function are well known, posttranscriptional regulatory mechanisms remain unclear. In this study, we show that the cytosolic RNA-binding protein clustered mitochondria homologue (CLUH) regulates the expression of a mitochondrial protein network supporting key metabolic programs required under nutrient deprivation. CLUH exerts its function by controlling the stability and translation of target messenger RNAs. In the absence of Cluh, mitochondria are severely depleted of crucial enzymes involved in catabolic energy-converting pathways. CLUH preserves oxidative mitochondrial function and glucose homeostasis, thus preventing death at the fetal-neonatal transition. In the adult liver, CLUH ensures maximal respiration capacity and the metabolic response to starvation. Our results shed new light on the posttranscriptional mechanisms controlling the expression of mitochondrial proteins and suggest novel strategies to tailor mitochondrial function to physiological and pathological conditions.

DOI: https://doi.org/10.1083/jcb.201607019

Dis Model Mech. 2017 Feb 10. pii: dmm.027540. [Epub ahead of print]

Overexpression of mitochondrial oxodicarboxylate carrier (ODC1) preserves oxidative phosphorylation in a yeast model of the Barth syndrome.

Maxence de Taffin de Tilques, Déborah Tribouillard-Tanvier, Emmanuel Tétaud, Eric Testet, Jean-Paul di Rago, Jean-Paul Lasserre.

Cardiolipin (CL) is a diglycerol phospholipid mostly found in mitochondria where it optimizes numerous processes including oxidative phosphorylation (OXPHOS). To function properly CL needs to be unsaturated, which requires the acyltransferase tafazzin. Loss-of-function mutations in this protein are responsible for the Barth syndrome (BTHS), presumably because of a diminished OXPHOS capacity. Here we show that overexpressing Odc1p, a conserved oxodicarboxylic acid carrier located in the mitochondrial inner membrane, fully restores oxidative phosphorylation in a yeast model (taz1Δ) of the Barth syndrome. The rescuing activity involves the recovery of a normal expression of key components that sustain oxidative phosphorylation, including the cytochrome c and complexes IV and III, that are strongly down regulated in taz1Δ yeast. Interestingly, overexpressing Odc1p was shown previously to rescue also yeast models of mitochondrial diseases caused by defects in the assembly of ATP synthase and by mutations in the MPV17 protein that result in the hepatocerebral mitochondrial DNA depletion syndrome. These findings define the transport of oxidicarboxylic acids across the inner membrane as a potential therapeutic target for a large spectrum of mitochondrial disease including BTHS.

Keywords: Barth syndrome; Human mitochondrial disease; cardiolipin remodeling; oxidative phosphorylation; oxodicarboxylic acid transport; tafazzin

DOI: https://doi.org/10.1242/dmm.027540

BMC Med Genet. 2017 Feb 10. 18(1): 14

A novel MTTT mutation m.15933G > A revealed in analysis of mitochondrial DNA in patients with suspected mitochondrial disease.

Heidi K Soini, Antti Väisänen, Mikko Kärppä, Reetta Hinttala, Laura Kytövuori, Jukka S Moilanen, Johanna Uusimaa, Kari Majamaa.

BACKGROUND: Mitochondrial diseases present with variable multi-organ symptoms. Common disease-causing mutations in mitochondrial DNA (mtDNA) are regularly screened in diagnostic work-up, but novel mutations may remain unnoticed.
METHODS: Patients (N = 66) with a clinical suspicion of mitochondrial disease were screened for their mtDNA coding region using conformation sensitive gel electrophoresis and sequencing. Long-PCR was used to detect deletions followed by POLG1 sequencing in patients with multiple deletions.
RESULTS: We discovered three novel mtDNA variants that included m.8743G > C, m.11322A > G and m.15933G > A. The novel MTTT variant m.15933G > A is suggested to be pathogenic. Analysis revealed also multiple mtDNA deletions in two patients and five nonsynonymous variants that were putatively pathogenic according to in-silico prediction algorithms. In addition, a rare haplogroup H associated m.7585_7586insT variant was discovered.
CONCLUSIONS: Among patients with a suspected mitochondrial disease, a novel MTTT variant m.15933G > A was discovered and is suggested to be pathogenic. In addition, several putatively pathogenic nonsynonymous variants and rare variants were found. These findings highlight the importance of coding region mtDNA screening among patients with clinical features suggesting a mitochondrial disease, but who lack the common mitochondrial disease mutations.

Keywords: Insertion; MTTT; Mitochondrial disease; Multiple deletions; POLG1; mtDNA

DOI: https://doi.org/10.1186/s12881-017-0377-8

Trends Mol Med. 2017 Feb 07. pii: S1471-4914(17)30003-5. [Epub ahead of print]

Mitochondrial Dynamics: Coupling Mitochondrial Fitness with Healthy Aging.

David Sebastián, Manuel Palacín, Antonio Zorzano.

Aging is associated with a decline in mitochondrial function and the accumulation of abnormal mitochondria. However, the precise mechanisms by which aging promotes these mitochondrial alterations and the role of the latter in aging are still not fully understood. Mitochondrial dynamics is a key process regulating mitochondrial function and quality. Altered expression of some mitochondrial dynamics proteins has been recently associated with aging and with age-related alterations in yeast, Caenorhabditis elegans, mice, and humans. Here, we review the link between alterations in mitochondrial dynamics, aging, and age-related impairment. We propose that the dysregulation of mitochondrial dynamics leads to age-induced accumulation of unhealthy mitochondria and contributes to alterations linked to aging, such as diabetes and neurodegeneration.

DOI: https://doi.org/10.1016/j.molmed.2017.01.003

J Neurosci. 2017 Feb 10. pii: 1777-16. [Epub ahead of print]

Distinct effects of miR-210 reduction on neurogenesis: increased neuronal survival of inflammation but reduced proliferation associated with mitochondrial enhancement.

Ludmila A Voloboueva, Xiaoyun Sun, Lijun Xu, Yi-Bing Ouyang, Rona G Giffard.

Neurogenesis is essential to brain development, and plays a central role in the response to brain injury. Stroke and head trauma stimulate proliferation of endogenous neural stem cells (NSC). However, the survival of young neurons is sharply reduced by post-injury inflammation. Cellular mitochondria are critical to successful neurogenesis and are a major target of inflammatory injury. Mitochondrial protection was shown to improve survival of young neurons. This study tested whether reducing cellular microRNA-210 (miR-210) would enhance mitochondrial function and improve survival of young murine neurons under inflammatory conditions. Several studies have demonstrated the potential of miR-210 inhibition to enhance and protect mitochondrial function through upregulation of mitochondrial proteins. Here miR-210 inhibition significantly increased neuronal survival and protected the activity of mitochondrial enzymes cytochrome c oxidase and aconitase in differentiating NSC cultures exposed to inflammatory mediators. Unexpectedly, we found that reducing miR-210 significantly attenuated NSC proliferation upon induction of differentiation. Further investigation revealed that increased mitochondrial function suppresses the shift to primarily glycolytic metabolism and reduced mitochondrial length characteristic of dividing cells. Activation of AMPK-retinoblastoma signaling is important in NSC proliferation, and the reduction of this activation observed by miR-210 inhibition is one mechanism contributing to the reduced proliferation. Post-injury neurogenesis occurs as a burst of proliferation that peaks in days followed by migration and differentiation over weeks. Our studies suggest that mitochondrial protective miR-210 inhibition should be delayed until after the initial burst of proliferation, but could be beneficial during the prolonged differentiation stage.Significance Statement:Increasing the success of endogenous neurogenesis after brain injury holds therapeutic promise. Post-injury inflammation markedly reduces newborn neuron survival. This study found that enhancement of mitochondrial function by reducing microRNA-210 (miR-210) levels could improve survival of young neurons under inflammatory conditions. MiR-210 inhibition protected the activity of mitochondrial enzymes cytochrome c oxidase and aconitase. On the other hand, we observed decreased precursor cell proliferation likely due to suppression of the AMPK/retinoblastoma axis with miR-210 inhibition. Thus mitochondrial protection is a double-edged sword: early inhibition reduces proliferation, but inhibition later significantly increases neuroblast survival. This in part explains contradictory published reports of the effects of miR-210 on neurogenesis.

DOI: https://doi.org/10.1523/JNEUROSCI.1777-16.2017

Photomed Laser Surg. 2017 Feb 09.

Effects of Near-Infrared Light on Cerebral Bioenergetics Measured with Phosphorus Magnetic Resonance Spectroscopy.

Dionyssios Mintzopoulos, Timothy E Gillis, Clark E Tedford, Marc J Kaufman.

OBJECTIVE: Cerebral photobiomodulation (PBM) improves mood and cognition. Cerebral metabolic enhancement is a mechanism proposed to underlie PBM effects. No PBM studies to date have applied phosphorus magnetic resonance spectroscopy (31P MRS), which can be used to assess metabolic intermediates such as phosphocreatine (PCr) and adenosine triphosphate, the latter of which is elevated by PBM. Accordingly, we used 9.4 Tesla 31P MRS to characterize effects of single and repeat cerebral PBM treatments on metabolism. PBM was delivered to healthy adult beagles in the form of transcranial laser treatment (TLT) at a wavelength of 808 nm, which passes safely through the skull and activates cytochrome C oxidase, a mitochondrial respiratory chain enzyme.
METHODS: Isoflurane-anesthetized subjects (n = 4) underwent a baseline 31P MRS scan followed by TLT applied sequentially for 2 min each to anterior and posterior cranium midline locations, to irradiate the dorsal cortex. Subjects then underwent 31P MRS scans for 2 h to assess acute TLT effects. After 2 weeks of repeat TLT (3 times/week), subjects were scanned again with 31P MRS to characterize effects of repeat TLT.
RESULTS: TLT did not induce acute 31P MRS changes over the course of 2 h in either scan session. However, after repeat TLT, the baseline PCr/β-nucleoside triphosphate ratio was higher than the scan 1 baseline (p < 0.0001), an effect attributable to increased PCr level (p < 0.0001).
CONCLUSIONS: Our findings are consistent with reports that bioenergetic effects of PBM can take several hours to evolve. Thus, in vivo 31P MRS may be useful for characterizing bioenergetic effects of PBM in brain and other tissues.

Keywords: adenosine triphosphate; cerebral metabolism; cytochrome C oxidase; low-level laser therapy; major depression; near-infrared light; phosphocreatine; phosphorus magnetic resonance spectroscopy; photobiomodulation

DOI: https://doi.org/10.1089/pho.2016.4238