bims-mitost 2019-04-07 papers

Issue of 2019–04–07
three papers selected by
Yvonne Will, Scientia-Consultants LLC

FASEB J. 2019 Apr 05. fj201802723R

Statin-dependent modulation of mitochondrial metabolism in cancer cells is independent of cholesterol content.

Charleston F Christie, Diana Fang, Elizabeth G Hunt, Morgan E Morris, Amandine Rovini, Kareem A Heslop, Gyda C Beeson, Craig C Beeson, Eduardo N Maldonado.

Statins, widely used to treat hypercholesterolemia, inhibit the 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme of de novo cholesterol (Chol) synthesis. Statins have been also reported to slow tumor progression. In cancer cells, ATP is generated both by glycolysis and oxidative phosphorylation. Mitochondrial membrane potential (ΔΨ), a readout of mitochondrial metabolism, is sustained by the oxidation of respiratory substrates in the Krebs cycle to generate NADH and flavin adenine dinucleotide, which are further oxidized by the respiratory chain. Here, we studied the short-term effects of statins (3-24 h) on mitochondrial metabolism on cancer cells. Lovastatin (LOV) and simvastatin (SIM) increased ΔΨ in HepG2 and Huh7 human hepatocarcinoma cells and HCC4006 human lung adenocarcinoma cells. Mitochondrial hyperpolarization after LOV and SIM was dose and time dependent. Maximal increase in ΔΨ occurred at 10 µM and 24 h for both statins. The structurally unrelated atorvastatin also hyperpolarized mitochondria in HepG2 cells. Cellular and mitochondrial Chol remained unchanged after SIM. Both LOV and SIM decreased basal respiration, ATP-linked respiration, and ATP production. LOV and SIM did not change the rate of lactic acid production. In summary, statins modulate mitochondrial metabolism in cancer cells independently of the Chol content in cellular membranes without affecting glycolysis.-Christie, C. F., Fang, D., Hunt, E. G., Morris, M. E., Rovini, A., Heslop, K. A., Beeson, G. C., Beeson, C. C., Maldonado, E. N. Statin-dependent modulation of mitochondrial metabolism in cancer cells is independent of cholesterol content.

Keywords: glycolysis; lovastatin; mitochondrial membrane potential; oxidative phosphorylation; simvastatin

DOI: https://doi.org/10.1096/fj.201802723R

Curr Protein Pept Sci. 2019 Apr 01.

Mitochondrial dysfunction in skeletal muscle pathologies.

Johanna Abrigo, Felipe Simon, Daniel Cabrera, Cristian Vilos, Claudio Cabello-Verrugio.

Several molecular mechanisms are involved in the regulation of skeletal muscle function. Among them can be identified mitochondrial activity. The mitochondria is an important and essential organelle in the skeletal muscle that is involved in metabolic regulation and ATP production, which are two key elements of muscle contractibility and plasticity. Thus, in this review, we present the critical and recent antecedents regarding the mechanisms through which mitochondrial dysfunction can be involved in the generation and development of skeletal muscle pathologies, its contribution to detrimental functioning in skeletal muscle and its crosstalk with other typical signaling pathways related to muscle diseases. In addition, an update on the development of new strategies with therapeutic potential to inhibit the deleterious impact of mitochondrial dysfunction in skeletal muscle is discussed.

Keywords: ROS; atrophy; dystrophy.; mitochondria; skeletal muscle

DOI: https://doi.org/10.2174/1389203720666190402100902

Ann Dermatol Venereol. 2019 Mar 28. pii: S0151-9638(19)30084-5. [Epub ahead of print]

[Dermatomyositis-like syndrome revealing statin-induced necrotizing autoimmune myopathy with anti-HMGCR antibodies].

M Merlant, C Fite, D Kottler, L Maisonobe, A Dossier, L Deschamps, V Descamps.

BACKGROUND: Statin-induced necrotizing autoimmune myopathy (NAM) has been recently characterized. Herein we report an accurate description of the clinical and histological characteristics of cutaneous rash associated with NAM.
PATIENTS AND METHODS: A 61-year-old woman presented a skin rash involving the face, the chest and the back of the hands with heliotropic distribution coupled with proximal symmetrical muscle weakness. Rosuvastatin had been introduced 8 months earlier. Creatinine kinase levels were dramatically raised. Screening for lupus and dermatomyositis antibodies were negative. The cutaneous histology was consistent with neutrophilic lupus while a muscle biopsy revealed no inflammation but showed necrotic and regenerative myofibres. Finally, antibodies directed against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) were found at high levels (1658UA/ml vs. normal<13.0UA/ml), resulting in diagnosis of necrotizing autoimmune myopathy (NAM). Intensive immunosuppressive therapy resulted in excellent improvement.
DISCUSSION: NAM is a severe acquired autoimmune myopathy characterised by severe proximal weakness and specific positive antibodies (anti-HMGCR or anti-signal recognition particle). It is classically associated with statin use. Some extra-muscular symptoms have been described in previous studies. We report the third accurate description of cutaneous rash associated with statin-induced NAM involving HMGCR antibodies. The skin rash was evocative of connective tissue disease and our diagnosis was based on immunology and muscle histology.
CONCLUSION: Dermatologists must be able to recognise this rare entity of "pseudo-dermatomyositis" and then discontinue statin intake if present and carry out further investigations consisting of muscle biopsy and serological tests.

Keywords: Anti HMGCR antibody; Anticorps anti-HMGCR; Autoimmune myopathy; Immunity; Myopathie auto-immune; Rosuvastatin; Rosuvastatine; Statin; Statine

DOI: https://doi.org/10.1016/j.annder.2018.12.010