Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis

Abstract

Objective Cerebral atrophy is a correlate of clinical progression in multiple sclerosis (MS). Mitochondria are now established to play a part in the pathogenesis of MS. Uniquely, mitochondria harbor their own mitochondrial DNA (mtDNA), essential for maintaining a healthy central nervous system. We explored mitochondrial respiratory chain activity and mtDNA deletions in single neurons from secondary progressive MS (SPMS) cases.Methods Ninety-eight snap-frozen brain blocks from 13 SPMS cases together with complex IV/complex II histochemistry, immunohistochemistry, laser dissection microscopy, long-range and real-time PCR and sequencing were used to identify and analyze respiratory-deficient neurons devoid of complex IV and with complex II activity.Results The density of respiratory-deficient neurons in SPMS was strikingly in excess of aged controls. The majority of respiratory-deficient neurons were located in layer VI and immediate subcortical white matter (WM) irrespective of lesions. Multiple deletions of mtDNA were apparent throughout the gray matter (GM) in MS. The respiratory-deficient neurons harbored high levels of clonally expanded mtDNA deletions at a single-cell level. Furthermore, there were neurons lacking mtDNA-encoded catalytic subunits of complex IV. mtDNA deletions sufficiently explained the biochemical defect in the majority of respiratory-deficient neurons.Interpretation These findings provide evidence that neurons in MS are respiratory-deficient due to mtDNA deletions, which are extensive in GM and may be induced by inflammation. We propose induced multiple deletions of mtDNA as an important contributor to neurodegeneration in MS.

Exploring the origins of grey matter damage in multiple sclerosis

“…Respiratory-deficient neurons with multiple deletions in mitochondrial DNA are distributed diffusely in the cortex of MS patients 122 .…”

Mitochondrial involvement in neurodegenerative diseases

“…A slow clonal expansion of these deletions would then lead to respiratory dysfunctions in hippocampal pyramidal neurons and interneurons causing cell death and intractable chronic epilepsy at adult age (54,84). Clonal expansions of mtDNA deletions have also been observed in patients with multiple sclerosis (MS) and are suggested to be an important contributor to neurodegeneration in MS (85,86). Here, chronic inflammation appears to trigger mtDNA mutagenesis and initiate clonal expansion.…”

Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons

“…Although most demyelinated axons compensate for loss of oligodendrocytes/myelin, additional insults to axonal mitochondria impair axonal metabolism, increase axonal Ca 2+ , and promote progressive disruption of mitochondrial function (11,12). Changes in axonal mitochondria have been described in chronically demyelinated axons in postmortem multiple sclerosis tissue, and include decreased expression of nuclear-encoded mitochondrial genes (13), reduced mitochondrial respiration (14), and genetic alterations in mitochondrial DNA (15). A vicious cycle of reduced ATP production and increased axonal Ca 2+ results in degeneration of the chronically demyelinated axon.…”