Showing papers by "Darius Ebrahimi-Fakhari published in 2017"

Linking mitochondrial dysfunction to neurodegeneration in lysosomal storage diseases

Abstract: Lysosomal storage diseases (LSD) are inborn errors of metabolism resulting in multisystem disease. Central nervous system involvement, often with progressive neurodegeneration, accounts for a large portion of the morbidity and mortality seen in many LSD. Available treatments fail to prevent or correct neurologic symptoms and decline. Emerging evidence points to an important role for mitochondrial dysfunction in the pathogenesis and progression of LSD-associated neurodegeneration. Mitochondrial dysfunction in LSD is characterized by alterations in mitochondrial mass, morphology and function. Disturbed mitochondrial metabolism in the CNS may lead to excessive production of mitochondrial reactive oxygen species and dysregulated calcium homeostasis. These metabolic disturbances ultimately result in mitochondria-induced apoptosis and neuronal degeneration. Here, we review the current evidence for mitochondrial dysfunction in neuronal models of seven LSD, including GM1-gangliosidosis, mucopolysaccharidosis IIIC, multiple sulfatase deficiency, Krabbe disease, Gaucher disease, Niemann Pick disease type C and the neural ceroid lipofuscinoses and outline current experimental therapies aimed at restoring mitochondrial function and neuroprotection in LSD.

p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis.

Abstract: p62/sequestosome-1 (SQSTM1) is a multifunctional adaptor protein and autophagic substrate that accumulates in cells with hyperactive mTORC1, such as kidney cells with mutations in the tumor suppressor genes tuberous sclerosis complex (TSC)1 or TSC2 Here we report that p62 is a critical mediator of TSC2-driven tumorigenesis, as Tsc2+/- and Tsc2f/f Ksp-CreERT2+ mice crossed to p62-/- mice were protected from renal tumor development Metabolic profiling revealed that depletion of p62 in Tsc2-null cells decreased intracellular glutamine, glutamate, and glutathione (GSH) p62 positively regulated the glutamine transporter Slc1a5 and increased glutamine uptake in Tsc2-null cells We also observed p62-dependent changes in Gcl, Gsr, Nqo1, and Srxn1, which were decreased by p62 attenuation and implicated in GSH production and utilization p62 attenuation altered mitochondrial morphology, reduced mitochondrial membrane polarization and maximal respiration, and increased mitochondrial reactive oxygen species and mitophagy marker PINK1 These mitochondrial phenotypes were rescued by addition of exogenous GSH and overexpression of Sod2, which suppressed indices of mitochondrial damage and promoted growth of Tsc2-null cells Finally, p62 depletion sensitized Tsc2-null cells to both oxidative stress and direct inhibition of GSH biosynthesis by buthionine sulfoximine Our findings show how p62 helps maintain intracellular pools of GSH needed to limit mitochondrial dysfunction in tumor cells with elevated mTORC1, highlighting p62 and redox homeostasis as nodal vulnerabilities for therapeutic targeting in these tumors Cancer Res; 77(12); 3255-67 ©2017 AACR

Using tuberous sclerosis complex to understand the impact of MTORC1 signaling on mitochondrial dynamics and mitophagy in neurons.

Abstract: Constitutive activation of the MTOR pathway is a key feature of defects in the tuberous sclerosis complex and other genetic neurodevelopmental diseases, collectively referred to as MTORopathies. MTORC1 hyperactivity promotes anabolic cell functions such as protein synthesis, yet at the same time catabolic processes such as macroautophagy/autophagy are suppressed. Mitochondria are major substrates of autophagy; however, their role in MTORopathies remains largely undefined. Here, we review our recent study showing that several aspects of mitochondrial function, dynamics and turnover are critically impaired in neuronal models of TSC. We discuss the relevance of these findings to neurological manifestations associated with TSC and speculate on autophagy as a novel treatment target for MTORopathies.

Combination Clearance Therapy and Barbiturate Coma for Severe Carbamazepine Overdose.

Abstract: A 15-year-old female subject presented comatose, in respiratory failure and shock, after the intentional ingestion of ∼280 extended-release 200-mg carbamazepine tablets with a peak serum concentration of 138 µg/mL (583.74 µmol/L). The patient developed clinical seizures and an EEG pattern of stimulus-induced rhythmic, periodic, or ictal discharges, suggestive of significant cortical dysfunction. Due to the extremely high drug serum concentration and clinical instability, a combination of therapies was used, including lipid emulsion therapy, plasmapheresis, hemodialysis, continuous venovenous hemodiafiltration, and endoscopic intestinal decontamination. The patient's elevated serum lactate level with a high mixed venous saturation suggested possible mitochondrial dysfunction, prompting treatment with barbiturate coma to reduce cerebral metabolic demand. The serum carbamazepine concentration declined steadily, with resolution of lactic acidosis, no long-term end-organ damage, and return to baseline neurologic function. The patient was eventually discharged in her usual state of health. In the laboratory, we demonstrated in vitro that the active metabolite of carbamazepine hyperpolarized the mitochondrial membrane potential, supporting the hypothesis that the drug caused mitochondrial dysfunction. We thus successfully treated a life-threatening carbamazepine overdose with a combination of modalities. Future studies are required to validate this aggressive approach. The occurrence of mitochondrial dysfunction must be confirmed in patients with carbamazepine toxicity and the need to treat it validated.