Identification of a novel heterozygous guanosine monophosphate reductase (
            GMPR
            ) variant in a patient with a late‐onset disorder of mitochondrial DNA maintenance

Various recent developments of relevance to Parkinson's disease (PD) are discussed and integrated into a comprehensive hypothesis on the nature, origin and inter-cellular mode of propagation of late-onset sporadic PD. We propose to define sporadic PD as a characteristic pathological deviation in the global gene expression program of a cell: the PD expression-state, or PD-state for short. Although a universal cell-generic state, the PD-state deviation would be particularly damaging in a neuronal context, ultimately leading to neuron death and the ensuing observed clinical signs. We review why age accumulated damage caused by oxidative stress in mitochondria could be the trigger for a primordial cell to shift to the PD-state. We put forward hematopoietic cells could be the first to acquire the PD-state, at hematopoiesis, from the disruption in reactive oxygen species (ROS) homeostasis that arises with age in the hematopoietic stem-cell niche. We argue why, nonetheless, such a process is unlikely to explain the shift to the PD-state of all the subsequently affected cells in a patient, thus indicating the existence of a distinct mechanism of propagation of the PD-state. We highlight recent findings on the intercellular exchange of mitochondrial DNA and the ability of mitochondrial DNA to modulate the cellular global gene expression state and propose this could form the basis for the intercellular propagation of the PD-state.

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Complete loss of mitofusins leads to gross respiratory chain dysfunction due to aberrant mitochondrial DNA maintenance and distribution

Biochimica et Biophysica Acta (BBA) - Bioenergetics ◽

10.1016/j.bbabio.2016.04.417 ◽

2016 ◽

Vol 1857 ◽

pp. e27

Author(s):

Eduardo Silva Ramos ◽

Elisa Motori ◽

Christian Brüser ◽

Inge Kühl ◽

Benedetta Ruzzenente ◽

...

Keyword(s):

Mitochondrial Dna ◽

Respiratory Chain ◽

Complete Loss ◽

Dna Maintenance

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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.

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