Mitochondria are semiautonomous cell organelles which possess their own genome (mtDNA) but nonetheless depend on the import of nuclear-encoded proteins. In recent years, several mutations of mtDNA have been associated with specific diseases of the muscles and nervous system. In 1993, the A>G point mutation at position 3243 of the mtDNA, until then a prominent genetic marker for mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), was detected in patients with progressive external ophthalmoplegia (PEO). Due to the divergent clinical presentations of MELAS and PEO, the presence of potential nuclear secondary mutations or so-called modifier genes had been suspected. Now it is well known that a bidirectional information flow between the mitochondrion and the cell nucleus exists and that nuclear gene expression adapts to the functional status of the mitochondria. However it remains unclear when and how the nucleus responds to changes or mutations of the mtDNA and if there are indeed disease-specific biomarker genes whose expression changes in case of mtDNA aberrations. This review article focuses on the most recent gene expression profiling studies in the field of classic mitochondrial disorders.