No evidence of ischemia in stroke-like lesions of mitochondrial POLG encephalopathy

•Vascularity is increased in acute and chronic brain lesions caused by POLG mutations.•Stroke-like lesions of POLG encephalopathy do not show an ischemic etiology.•Mitochondrial failure triggers neovascularization in POLG encephalopathy.

Stroke-like lesions are characteristically associated with mitochondrial encephalopathies such as those caused by mutations of polymerase gamma (POLG) and the m.3243A > G mitochondrial DNA (mtDNA) mutation. The combination of acute clinical onset, MRI and pathological abnormalities, have led to the suggestion that these lesions are ischemic. Here, we sought to determine the role of ischemia in the pathogenesis of mitochondrial stroke-like lesions. We performed a systematic study of cerebral blood vessel morphology, density and distribution in post mortem brain tissue from nine patients with POLG-encephalopathy and seven neurologically healthy controls. We found that patients had significantly higher cerebral vascular density than controls: this was more pronounced in areas of chronic neurodegeneration, where vascular density correlated with the severity of neuronal loss, but was also seen in acute lesions. Further, blood vessels were patent and, in acute lesions, dilated suggesting increased perfusion. In contrast to what would be expected in ischemia, stroke-like lesions were not pan-necrotic and were highly vascularized. Our results suggest that ischemia does not contribute to the pathogenesis of either the chronic neurodegeneration or acute lesions in POLG encephalopathy. Neovascularization and vascular dilatation does occur and suggests a compensatory response. We suggested the acute lesions are more likely to reflect energy insufficiency and our earlier studies suggest that this is driven in large part by seizure activity.