The maternal (F) and paternal (M) mitochondrial genomes of the mussel Mytilus galloprovincialis have diverged by about 20% in nucleotide sequence but retained identical gene content and gene arrangement and similar nucleotide composition and codon usage bias. Both lack the ATPase8 subunit gene, have two tRNAs for methionine and a longer open-reading frame for cox3 than seen in other mollusks. Between the F and M genomes, tRNAs are most conserved followed by rRNAs and protein-coding genes, even though the degree of divergence varies considerably among the latter. Divergence at nad3 is exceptionally low most likely because this gene includes the origin of transcription of the lagging strand (O(L)). Noncoding regions are the least conserved with the notable exception of the central domain of the main control region and a segment of another noncoding region immediately following nad3. The amino acid divergence (14%) of the two genomes is smaller than in two other pairs of conspecific genomes that are available in GenBank, that of the clam Venerupis philippinarum (34%) and of the fresh water mussel Inversidens japanensis (50%), suggesting that doubly uniparental inheritance of mtDNA emerged at different times in the three species or that there has been a relatively recent replacement of the male genome by the female in the Mytilus line. The latter hypothesis is supported from phylogenetic and population studies of Mytilidae. That the M genome contains a full complement of genes with no premature termination codons argues against it being a selfish element that rides with the sperm. It is shorter than the F by 118 bp, which apparently cannot account for the postulated replicative advantage of this genome over the F in male gonads. The high similarity of the two genomes explains why the F genome may assume the role of the M genome, but it does not exclude the possibility that for this to happen some M-specific sequences must be transferred on to the F genome by means of recombination. If such sequences exist they would most likely be located in noncoding regions.

Highlights d TOP2-mediated DNA fragility is linked to transcription and proximity to loop anchors d Loop-anchor DNA fragility correlates with transcriptional activity and directionality d Genes forming oncogenic fusions are highly transcribed and enriched at loop anchors d Formation of MLL fusions relies on the activities of both TOP2 isoforms

Summary The cellular responses induced by mitochondrial dysfunction remain elusive. Intrigued by the lack of almost any glomerular phenotype in patients with profound renal ischemia, we comprehensively investigated the primary sources of energy of glomerular podocytes. Combining functional measurements of oxygen consumption rates, glomerular metabolite analysis, and determination of mitochondrial density of podocytes in vivo , we demonstrate that anaerobic glycolysis and fermentation of glucose to lactate represent the key energy source of podocytes. Under physiological conditions, we could detect neither a developmental nor late-onset pathological phenotype in podocytes with impaired mitochondrial biogenesis machinery, defective mitochondrial fusion-fission apparatus, or reduced mtDNA stability and transcription caused by podocyte-specific deletion of Pgc-1α , Drp1 , or Tfam , respectively. Anaerobic glycolysis represents the predominant metabolic pathway of podocytes. These findings offer a strategy to therapeutically interfere with the enhanced podocyte metabolism in various progressive kidney diseases, such as diabetic nephropathy or focal segmental glomerulosclerosis (FSGS).