Redox regulation of protein misfolding, mitochondrial dysfunction, synaptic damage, and cell death in neurodegenerative diseases

Abstract Background Apoptosis-inducing factor (AIF), as a mitochondrial flavoprotein, plays a fundamental role in mitochondrial bioenergetics that is critical for cell survival and also mediates caspase-independent cell death once it is released from mitochondria and translocated to the nucleus under ischemic stroke or neurodegenerative diseases. Although alternative splicing regulation of AIF has been implicated, it remains unknown which AIF splicing isoform will be induced under pathological conditions and how it impacts mitochondrial functions and neurodegeneration in adult brain. Methods AIF splicing induction in brain was determined by multiple approaches including 5′ RACE, Sanger sequencing, splicing-specific PCR assay and bottom-up proteomic analysis. The role of AIF splicing in mitochondria and neurodegeneration was determined by its biochemical properties, cell death analysis, morphological and functional alterations and animal behavior. Three animal models, including loss-of-function harlequin model, gain-of-function AIF3 knockin model and conditional inducible AIF splicing model established using either Cre-loxp recombination or CRISPR/Cas9 techniques, were applied to explore underlying mechanisms of AIF splicing-induced neurodegeneration. Results We identified a nature splicing AIF isoform lacking exons 2 and 3 named as AIF3. AIF3 was undetectable under physiological conditions but its expression was increased in mouse and human postmortem brain after stroke. AIF3 splicing in mouse brain caused enlarged ventricles and severe neurodegeneration in the forebrain regions. These AIF3 splicing mice died 2–4 months after birth. AIF3 splicing-triggered neurodegeneration involves both mitochondrial dysfunction and AIF3 nuclear translocation. We showed that AIF3 inhibited NADH oxidase activity, ATP production, oxygen consumption, and mitochondrial biogenesis. In addition, expression of AIF3 significantly increased chromatin condensation and nuclear shrinkage leading to neuronal cell death. However, loss-of-AIF alone in harlequin or gain-of-AIF3 alone in AIF3 knockin mice did not cause robust neurodegeneration as that observed in AIF3 splicing mice. Conclusions We identified AIF3 as a disease-inducible isoform and established AIF3 splicing mouse model. The molecular mechanism underlying AIF3 splicing-induced neurodegeneration involves mitochondrial dysfunction and AIF3 nuclear translocation resulting from the synergistic effect of loss-of-AIF and gain-of-AIF3. Our study provides a valuable tool to understand the role of AIF3 splicing in brain and a potential therapeutic target to prevent/delay the progress of neurodegenerative diseases.

Download Full-text

Mitochondrial DNA–Related Mitochondrial Dysfunction in Neurodegenerative Diseases

Archives of Pathology & Laboratory Medicine ◽

10.5858/2002-126-0271-mdrmdi ◽

2002 ◽

Vol 126 (3) ◽

pp. 271-280

Author(s):

Russell H. Swerdlow

Keyword(s):

Cell Death ◽

Mitochondrial Dna ◽

Programmed Cell Death ◽

Neurodegenerative Diseases ◽

Mitochondrial Dysfunction ◽

Cell Lines ◽

Late Onset ◽

Cell Death Pathways ◽

Mitochondrial Genotype ◽

Cybrid Cell

Abstract Mitochondrial dysfunction occurs in several late-onset neurodegenerative diseases. Determining its origin and significance may provide insight into the pathogeneses of these disorders. Regarding origin, one hypothesis proposes mitochondrial dysfunction is driven by mitochondrial DNA (mtDNA) aberration. This hypothesis is primarily supported by data from studies of cytoplasmic hybrid (cybrid) cell lines, which facilitate the study of mitochondrial genotype-phenotype relationships. In cybrid cell lines in which mtDNA from persons with certain neurodegenerative diseases is assessed, mitochondrial physiology is altered in ways that are potentially relevant to programmed cell death pathways. Connecting mtDNA-related mitochondrial dysfunction with programmed cell death underscores the crucial if not central role for these organelles in neurodegenerative pathophysiology. This review discusses the cybrid technique and summarizes cybrid data implicating mtDNA-related mitochondrial dysfunction in certain neurodegenerative diseases.

Download Full-text

S-Nitrosylation of Critical Protein Thiols Mediates Protein Misfolding and Mitochondrial Dysfunction in Neurodegenerative Diseases

Antioxidants and Redox Signaling ◽

10.1089/ars.2010.3570 ◽

2011 ◽

Vol 14 (8) ◽

pp. 1479-1492 ◽

Cited By ~ 59

Author(s):

Tomohiro Nakamura ◽

Stuart A. Lipton

Keyword(s):

Neurodegenerative Diseases ◽

Mitochondrial Dysfunction ◽

Protein Misfolding ◽

Protein Thiols

Download Full-text

Cell death: protein misfolding and neurodegenerative diseases

APOPTOSIS ◽

10.1007/s10495-008-0301-y ◽

2009 ◽

Vol 14 (4) ◽

pp. 455-468 ◽

Cited By ~ 120

Author(s):

Tomohiro Nakamura ◽

Stuart A. Lipton

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Protein Misfolding ◽

Cell Death Protein

Download Full-text

Redox Reactions Induced by Nitrosative Stress Mediate Protein Misfolding and Mitochondrial Dysfunction in Neurodegenerative Diseases

Molecular Neurobiology ◽

10.1007/s12035-010-8113-9 ◽

2010 ◽

Vol 41 (2-3) ◽

pp. 55-72 ◽

Cited By ~ 87

Author(s):

Zezong Gu ◽

Tomohiro Nakamura ◽

Stuart A. Lipton

Keyword(s):

Neurodegenerative Diseases ◽

Mitochondrial Dysfunction ◽

Protein Misfolding ◽

Redox Reactions ◽

Nitrosative Stress

Download Full-text

Air Pollution-Related Brain Metal Dyshomeostasis as a Potential Risk Factor for Neurodevelopmental Disorders and Neurodegenerative Diseases

Atmosphere ◽

10.3390/atmos11101098 ◽

2020 ◽

Vol 11 (10) ◽

pp. 1098

Author(s):

Deborah Cory-Slechta ◽

Marissa Sobolewski ◽

Günter Oberdörster

Keyword(s):

Oxidative Stress ◽

Air Pollution ◽

Cell Death ◽

Neurodegenerative Diseases ◽

Mitochondrial Dysfunction ◽

Neurodevelopmental Disorders ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Autism Spectrum ◽

System Structure

Increasing evidence links air pollution (AP) exposure to effects on the central nervous system structure and function. Particulate matter AP, especially the ultrafine (nanoparticle) components, can carry numerous metal and trace element contaminants that can reach the brain in utero and after birth. Excess brain exposure to either essential or non-essential elements can result in brain dyshomeostasis, which has been implicated in both neurodevelopmental disorders (NDDs; autism spectrum disorder, schizophrenia, and attention deficit hyperactivity disorder) and neurodegenerative diseases (NDGDs; Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis). This review summarizes the current understanding of the extent to which the inhalational or intranasal instillation of metals reproduces in vivo the shared features of NDDs and NDGDs, including enlarged lateral ventricles, alterations in myelination, glutamatergic dysfunction, neuronal cell death, inflammation, microglial activation, oxidative stress, mitochondrial dysfunction, altered social behaviors, cognitive dysfunction, and impulsivity. Although evidence is limited to date, neuronal cell death, oxidative stress, and mitochondrial dysfunction are reproduced by numerous metals. Understanding the specific contribution of metals/trace elements to this neurotoxicity can guide the development of more realistic animal exposure models of human AP exposure and consequently lead to a more meaningful approach to mechanistic studies, potential intervention strategies, and regulatory requirements.

Download Full-text