Mitochondrial roles in antiviral immunity modify manifestations of neurological diseases

Viking-age gene mutation alters viral defense

Why a disease manifests at a certain age, and what kind of triggers may be involved, are still open questions. Recent data indicate that mitochondria, the cellular centers of energy and nutrient metabolism, have new important roles in protecting cells from both internal and external stresses. Importantly, a novel role of mitochondria in strengthening the immune system has been recognized, but the relevance of these functions for human diseases has been unclear.

The current study shows that deficient mitochondrial functions in immune defense are connected to the manifestation of brain diseases and sometimes also liver dysfunction. A multidisciplinary team led by academy professor Anu Suomalainen discovered that a genetic variant affecting the function of mitochondrial POLG enzyme delays the detection of viral infection, leading to delayed severe inflammatory reactions damaging the brain and liver.

The POLG variant originates from a single individual dating back to Viking times and has spread to populations of European origin. Especially Northern European countries show high carrier frequencies: one in a hundred individuals in Finland and Norway. If a subject inherits the POLG-variant from both parents, a neurological disease, MIRAS (mitochondrial recessive ataxia syndrome), manifests. However, the ages of onset and manifestations of MIRAS are highly variable, raising the question of whether the disease is triggered by additional factors.

Using a variable set of model systems, the team shows that the POLG variant leads to a weakened initial immune activation in response to viral infection, followed by a delayed, overactivated inflammation damaging the brain and liver. The scientists suggest that this mechanism explains why some MIRAS patients manifest in teenagers with severe epilepsy, while some other patients with the same genetic background show disease signs years or even decades later, as motor coordination defects or Parkinson's disease.

"Our results indicate that external factors, such as viral infections, can modify manifestation and age-of-onset of neurological diseases," postdoctoral scientist Yilin Kang comments. "Identification of susceptibility factors and triggering mechanisms are valuable targets for new therapy developments. The current findings indicate the importance of new mitochondrial functions in maintaining brain health."