The mitochondrial import gene tomm22 is specifically required for hepatocyte survival and provides a liver regeneration model

Abstract

SUMMARYUnderstanding liver development should lead to greater insights into liver diseases and improve therapeutic strategies. In a forward genetic screen for genes regulating liver development in zebrafish, we identified a mutant -oliver -that exhibits liver-specific defects. In oliver mutants, the liver is specified, bile ducts form and hepatocytes differentiate. However, the hepatocytes die shortly after their differentiation, and thus the resulting mutant liver consists mainly of biliary tissue. We identified a mutation in the gene encoding translocase of the outer mitochondrial membrane 22 (Tomm22) as responsible for this phenotype. Mutations in tomm genes have been associated with mitochondrial dysfunction, but most studies on the effect of defective mitochondrial protein translocation have been carried out in cultured cells or unicellular organisms. Therefore, the tomm22 mutant represents an important vertebrate genetic model to study mitochondrial biology and hepatic mitochondrial diseases. We further found that the temporary knockdown of Tomm22 levels by morpholino antisense oligonucleotides causes a specific hepatocyte degeneration phenotype that is reversible: new hepatocytes repopulate the liver as Tomm22 recovers to wild-type levels. The specificity and reversibility of hepatocyte ablation after temporary knockdown of Tomm22 provides an additional model to study liver regeneration, under conditions where most hepatocytes have died. We used this regeneration model to analyze the signaling commonalities between hepatocyte development and regeneration.

PGE2-regulated wnt signaling and N -acetylcysteine are synergistically hepatoprotective in zebrafish acetaminophen injury

“…Wnt activation is involved in many instances of organ repair, including liver regeneration after surgical resection (12,24) or in the setting of mitochondrial dysfunction (35). Recently, Wnt signaling was found to be activated after APAP injury in murine livers (25), consistent with our work.…”

Conditional control of gene function by an invertible gene trap in zebrafish

“…The pronounced defects in the retina, liver, and intestines are likely due to the rapid growth in these tissues during development, which likely requires elevated mitochondrial activity. Similar defects have been reported for mutations in the mitochondrial import gene tomm22 (23). Although the liver defect is the most prominent defect exhibited by supv3l1 GtT/GtT mutants, it is not solely responsible for larval lethality, as mutants with rescued supv3l1 still fail to thrive.…”

Tom70 serves as a molecular switch to determine pathological cardiac hypertrophy

“…Herein, we identified a marked reduction in Tom70 among the Tom complex proteins in pathological hypertrophic cardiomyocytes from different species and discovered that Tom70 knockdown induced the pathological hypertrophic growth of mammalian primary cardiomyocytes and zebrafish hearts without affecting fibroblast transdifferentiation into cardiomyocytes (Supplementary information, Figure S1) or the expression of early cardiogenesis markers (Supplementary information, Figure S2F). However, the Tom70-mediated cardiac hypertrophy does not involve Tom20/22 receptors: Tom20 defect caused a lethal developmental defect (Supplementary information, Figure S6), and Tom22 knockdown did not induce obvious abnormalities in the heart [22]. Thus, our study provides evidence that Tom70 exerts an evo- A balanced activity of the fusion and fission machineries shapes the mitochondrial compartment, and the behavior of mitochondria allows the cell to respond to ever-changing stressful conditions [23].…”