The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This statement is intended for physicians who are engaged in the diagnosis and management of these patients. Working group members were appointed by the Mitochondrial Medicine Society. The panel included members with several different areas of expertise. The panel members utilized surveys and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Consensus-based recommendations are provided for the routine care and management of patients with primary genetic mitochondrial disease.

AMP-activated protein kinase (AMPK) is an important energy sensor that may be critical in regulating renal lipid accumulation. To evaluate the role of AMPK in mediating renal lipid accumulation, C57BL/6J mice were randomized to a standard diet, a high-fat diet, or a high-fat diet plus AICAR (an AMPK activator) for 14 weeks. Renal functional and structural studies along with electron microscopy were performed. Mice given the high-fat diet had proximal tubule injury with the presence of enlarged clear vacuoles, and multilaminar inclusions concurrent with an increase of tissue lipid and overloading of the lysosomal system. The margins of the clear vacuoles were positive for the endolysosomal marker, LAMP1, suggesting lysosome accumulation. Characterization of vesicles by special stains (Oil Red O, Nile Red, Luxol Fast Blue) and by electron microscopy showed they contained onion skin-like accumulations consistent with phospholipids. Moreover, cholesteryl esters and phosphatidylcholine-containing phospholipids were significantly increased in the kidneys of mice on a high-fat diet. AMPK activation with chronic AICAR treatment prevented the clinical and structural effects of high-fat diet. Thus, high-fat diet contributes to a dysfunction of the lysosomal system and altered lipid metabolism characterized by cholesterol and phospholipid accumulation in the kidney. AMPK activation normalizes the changes in renal lipid content despite chronic exposure to lipid challenge.

Autism spectrum disorders (ASDs) are caused by both genetic and environmental factors. Mitochondria act to connect genes and environment by regulating gene-encoded metabolic networks according to changes in the chemistry of the cell and its environment. Mitochondrial ATP and other metabolites are mitokines—signaling molecules made in mitochondria—that undergo regulated release from cells to communicate cellular health and danger to neighboring cells via purinergic signaling. The role of purinergic signaling has not yet been explored in autism spectrum disorders. We used the maternal immune activation (MIA) mouse model of gestational poly(IC) exposure and treatment with the non-selective purinergic antagonist suramin to test the role of purinergic signaling in C57BL/6J mice. We found that antipurinergic therapy (APT) corrected 16 multisystem abnormalities that defined the ASD-like phenotype in this model. These included correction of the core social deficits and sensorimotor coordination abnormalities, prevention of cerebellar Purkinje cell loss, correction of the ultrastructural synaptic dysmorphology, and correction of the hypothermia, metabolic, mitochondrial, P2Y2 and P2X7 purinergic receptor expression, and ERK1/2 and CAMKII signal transduction abnormalities. Hyperpurinergia is a fundamental and treatable feature of the multisystem abnormalities in the poly(IC) mouse model of autism spectrum disorders. Antipurinergic therapy provides a new tool for refining current concepts of pathogenesis in autism and related spectrum disorders, and represents a fresh path forward for new drug development.