Acute mitochondrial encephalopathy reflects neuronal energy failure irrespective of which genome the genetic defect...

Mitochondrial dysfunction and disease may arise as a result of mutations in either the mitochondrial genome itself or nuclear encoded genes involved in mitochondrial homeostasis and function. Irrespective of which genome is affected, mitochondrial encephalopathies share clinical and biochemical features suggesting common pathophysiological pathways. Two common paradigms of mitochondrial encephalopathy are mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes caused by maternally transmitted mutations of mitochondrial DNA and mitochondrial spinocerebellar ataxia and epilepsy caused by recessively inherited mutations of the nuclear-encoded DNA polymerase gamma, which replicates and repairs the mitochondrial genome. We studied and compared the disease mechanisms involved in these two syndromes. Despite having different genetic origins, their pathophysiological pathways converge on one critical event, damage to the respiratory chain leading to insufficient energy to maintain cellular homeostasis. In the central nervous system, this appears to cause selective neuronal damage leading to the development of lesions that mimic ischaemic damage, but which lack evidence of decreased tissue perfusion. Although these stroke-like lesions may expand or regress dynamically, the critical factor that dictates prognosis is the presence of epilepsy. Epileptic seizures increase the energy requirements of the metabolically already compromised neurons establishing a vicious cycle resulting in worsening energy failure and neuronal death. We believe that it is this cycle of events that determines outcome and which provides us with a mechanistic structure to understand the pathophysiology of acute mitochondrial encephalopathies and plan future treatments.