Causative Role for Defective Expression of MIEAP in Accumulation of Mitochondria in Thyroid Oncocytic Cell Tumors.

Oncocytic cell tumor of the thyroid is composed of large polygonal cells with eosinophilic cytoplasm that is rich in mitochondria. These tumors frequently have the mutations in mitochondrial DNA encoding the mitochondrial electron transport system complex I. However, the mechanism for accumulation of abnormal mitochondria is unknown. A non-canonical mitophagy system has recently been identified, and mitochondria-eating protein (MIEAP) plays a key role in this system. We therefore hypothesized that accumulation of abnormal mitochondria could be attributed to defective MIEAP expression in these tumors. We first show that MIEAP was expressed in all the conventional thyroid follicular adenomas (FAs)/adenomatous goiters (AGs) but not in oncocytic FAs/AGs, while its expression was defective not only oncocytic thyroid cancers but also in the majority of conventional thyroid cancers. MIEAP expression was not correlated with methylation status of 5'-untranslated region of the gene. Our functional analysis demonstrated that exogenously induced MIEAP but not PARK2 reduced the amounts of abnormal mitochondria, as demonstrated by decreased reactive oxygen species levels, mitochondrial DNA/nuclear DNA ratios and cytoplasmic acidification. Therefore, together with previous studies showing that impaired mitochondrial function triggers compensatory mitochondrial biogenesis that causes an increase in the amounts of mitochondria, we would like to conclude that, in oncocytic cell tumors of the thyroid, increased abnormal mitochondria cannot be efficiently eliminated because of a loss of MIEAP expression, i.e., impaired MIEAP-mediated non-canonical mitophagy.