A novel lysosome-to-mitochondria signaling pathway disrupted by amyloid-{beta} oligomers

The mechanisms of mitochondrial dysfunction in Alzheimer's disease are incompletely understood. Using two-photon fluorescence lifetime microscopy of the coenzymes, NADH and NADPH, and tracking brain oxygen metabolism with multi-parametric photoacoustic microscopy, we show that activation of lysosomal mechanistic target of rapamycin complex 1 (mTORC1) by insulin or amino acids stimulates mitochondrial activity and regulates mitochondrial DNA synthesis in neurons. Amyloid-β oligomers, which are precursors of amyloid plaques in Alzheimer's disease brain and stimulate mTORC1 protein kinase activity at the plasma membrane but not at lysosomes, block this Nutrient-induced Mitochondrial Activity (NiMA) by a mechanism dependent on tau, which forms neurofibrillary tangles in Alzheimer's disease brain. NiMA was also disrupted in fibroblasts derived from two patients with tuberous sclerosis complex, a genetic disorder that causes dysregulation of lysosomal mTORC1. Thus, lysosomal mTORC1 couples nutrient availability to mitochondrial activity and links mitochondrial dysfunction to Alzheimer's disease by a mechanism dependent on the soluble building blocks of the poorly soluble plaques and tangles.
Source: EMBO Journal - Category: Molecular Biology Authors: Tags: Autophagy & Cell Death, Metabolism, Neuroscience Articles Source Type: research

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Publication date: Available online 16 November 2019Source: Molecular Aspects of MedicineAuthor(s): Christos ChinopoulosAbstractNeurometabolic disorders stem from errors in metabolic processes yielding a neurological phenotype. A subset of those disorders encompasses mitochondrial abnormalities partially due to mitochondrial DNA (mtDNA) depletion. mtDNA depletion can be attributed to inheritance, spontaneous mutations or acquired from drug-related toxicities. In the armamentarium of diagnostic procedures, mtDNA quantification is a standard for disease classification. However, alterations in mtDNA obtained from peripheral ti...
Source: Molecular Aspects of Medicine - Category: Molecular Biology Source Type: research
ConclusionsIn skeletal muscle, GSK-3β inactivation causes dephosphorylation and nuclear translocation of TFEB resulting in TFEB-dependent induction of Pgc-1α expression.
Source: Biochimica et Biophysica Acta (BBA) Molecular Cell Research - Category: Molecular Biology Source Type: research
Publication date: Available online 16 November 2019Source: PeptidesAuthor(s): Dipak Sarnobat, R. Charlotte Moffett, Victor A. Gault, Neil Tanday, Frank Reimann, Fiona M. Gribble, Peter R. Flatt, Nigel IrwinAbstractEnzyme-resistant long-acting forms of the gut-derived peptide hormones, glucose-dependent insulinotropic polypeptide (GIP), xenin and oxyntomodulin (Oxm) have been generated, and exert beneficial effects on diabetes control and pancreatic islet architecture. The current study has employed alpha-cell lineage tracing in GluCreERT2;ROSA26-eYFP transgenic mice to investigate the extent to which these positive pancrea...
Source: Peptides - Category: Biochemistry Source Type: research
In this study we analyzed the whole mtDNA sequence in six LHON families from Serbian population. The mtDNA sequencing was performed by Sanger’s method and various bioinformatic tools were used for analysis of detected mutations. LHON patients carry all three (m.3460G>A, m.11778G>A and m.14484T>C) primary mutations, together with numerous secondary mtDNA mutations. Four novel mutations (m.4516G>A, m.8779C>T, m.13138G>A and m.15986insG) in four different families were discovered. The m.8779C>T and m.13138G>A mutations could have a potential influence on LHON symptoms, but the issue of effect of ...
Source: Mitochondrion - Category: Biochemistry Source Type: research
Publication date: Available online 15 November 2019Source: Chemico-Biological InteractionsAuthor(s): Paula Roberta da Silva, Jamerson Ferreira de Oliveira, Anekécia Lauro da Silva, Camila Marques Queiroz, Ana Paula Sampaio Feitosa, Denise Maria Figueiredo Araújo Duarte, Aline Caroline da Silva, Maria Carolina Accioly Brelaz de Castro, Valéria Rêgo Alves Pereira, Rosali Maria Ferreira da Silva, Luiz Carlos Alves, Fábio André Brayner dos Santos, Maria do Carmo Alves de LimaAbstractParasitic diseases still represent serious public health problems, since the high and steady emergence of...
Source: Chemico Biological Interactions - Category: Biochemistry Source Type: research
ConclusionsThis study demonstrates biomarker-based MCI prognosis and supports its role in clinical decision-making in daily practice.ResumenObjetivoEl objetivo de este estudio fue investigar el rol y pronóstico de los biomarcadores de enfermedad de Alzheimer en pacientes con diagnóstico clínico de deterioro cognitivo leve (DCL) en una clínica de memoria de Latinoamérica.MétodoOchenta y nueve pacientes con DCL, 43 con demencia tipo Alzheimer y 18 controles normales apareados por edad, sexo y escolaridad fueron estudiados con un extenso protocolo demográfico, neurológic...
Source: Neurologia - Category: Neurology Source Type: research
Conclusions: [TIMP-2] × [IGFBP7] and soluble urokinase-type plasminogen activator receptor are promising biomarker candidates for the risk stratification of septic acute kidney injury patients with the need for renal replacement therapy.
Source: Critical Care Medicine - Category: Emergency Medicine Tags: Online Clinical Investigations Source Type: research
CONCLUSIONS: Our results indicate that Alzheimer disease medication might contribute to a reduction of the LOS and the number of readmissions in PWD. PMID: 31722770 [PubMed - as supplied by publisher]
Source: Epidemiology and Psychiatric Sciences - Category: Psychiatry Tags: Epidemiol Psychiatr Sci Source Type: research
CONCLUSION: We found no evidence that long-term exposure to work-related sleep loss had resulted in cognitive decline or early dementia symptoms in this sample of retired maritime pilots. PMID: 31726459 [PubMed - as supplied by publisher]
Source: Dementia and Geriatric Cognitive Disorders - Category: Psychiatry Tags: Dement Geriatr Cogn Disord Source Type: research
CONCLUSION: The AD8 is a brief and sensitive screening instrument that may facilitate earlier and more accurate AD diagnosis in a variety of care settings. PMID: 31725472 [PubMed - as supplied by publisher]
Source: Alzheimer Disease and Associated Disorders - Category: Psychiatry Tags: Alzheimer Dis Assoc Disord Source Type: research
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