Slower Dynamics and Aged Mitochondria in Sporadic Alzheimer’s Disease

Author:

Martín-Maestro Patricia123ORCID,Gargini Ricardo1,García Esther12,Perry George4,Avila Jesús12ORCID,García-Escudero Vega125ORCID

Affiliation:

1. Centro de Biología Molecular “Severo Ochoa” (UAM-CSIC), Nicolás Cabrera, 1. Cantoblanco 28049 Madrid, Spain

2. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo, 5, 28031 Madrid, Spain

3. Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, 407 E 61st St. 1300 York Avenue, New York, NY 10065, USA

4. University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249-0667, USA

5. Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, UAM, Arzobispo Morcillo, 4, 28029 Madrid, Spain

Abstract

Sporadic Alzheimer’s disease corresponds to 95% of cases whose origin is multifactorial and elusive. Mitochondrial dysfunction is a major feature of Alzheimer’s pathology, which might be one of the early events that trigger downstream principal events. Here, we show that multiple genes that control mitochondrial homeostasis, including fission and fusion, are downregulated in Alzheimer’s patients. Additionally, we demonstrate that some of these dysregulations, such as diminished DLP1 levels and its mitochondrial localization, as well as reduced STOML2 and MFN2 fusion protein levels, take place in fibroblasts from sporadic Alzheimer’s disease patients. The analysis of mitochondrial network disruption using CCCP indicates that the patients’ fibroblasts exhibit slower dynamics and mitochondrial membrane potential recovery. These defects lead to strong accumulation of aged mitochondria in Alzheimer’s fibroblasts. Accordingly, the analysis of autophagy and mitophagy involved genes in the patients demonstrates a downregulation indicating that the recycling mechanism of these aged mitochondria might be impaired. Our data reinforce the idea that mitochondrial dysfunction is one of the key early events of the disease intimately related with aging.

Funder

National Institute on Minority Health and Health Disparities

Publisher

Hindawi Limited

Subject

Cell Biology,Aging,General Medicine,Biochemistry

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