Sea squirt alternative oxidase prevents lethal mitochondrial cardiomyopathy in a mouse model of GRACILE syndrome

Source: GMC

Scientists from the Folkhälsan Research Center in Helsinki, Finland, the German Mouse Clinic and colleagues from Sweden investigated, whether the activity of the alternative oxidase of Ciona intestinalis (AOX) can bypass the OXPHOS defect and ameliorates the disease manifestations in a genetic mouse model of CIII deficiency. The results of the extensive study was published recently in EMBO Molecular Medicine.

Mitochondrial disorders are the most common class of inherited errors of metabolism. In patients with CIII (ubiquinol:cytochrome c oxidoreductase) deficiency the gene BCS1L is most frequently affected. The resulting impairment of CIII enzymatic activity leads to a wide variety of clinical manifestations with the GRACILE syndrome as it’s most severe. The rare disease is characterized by fetal growth restriction (GR), aminoaciduria (A), cholestasis (C), iron overload (I), lactacidosis (L), and early death (E). It has a prevalence of 1/1 000 000 and an incidence in Finland of 1/50 000 births.

Mice homozygous for the patient mutation Bcs1lA232G, which recapitulates many of the manifestations related to human GRACILE syndrome, survived only 7 month and died of cardiomyopathy. Recently it was published that the non-mammalian AOX can bypass the blockade of the mitochondrial Complex III-IV of the respiratory chain and did not have any impact in healthy mice (Szibor et al., 2017). AOX was crossed to this mouse model of CIII deficiency and the team of researchers analyzed all clinically relevant organ systems at early and late onset time points of the diseases manifestation. The homozygous mice harboring the AOX transgene lived longer (approx. 19 month) and did not develop signs of cardiomyopathy. In addition, AOX also ameliorated the severe kidney disease and focal astrogliosis of the brain in the homozygotes, but did not improve the liver function and several other disease symptoms suggesting different disease mechanism in different tissues. The abnormal ultrastructure of mitochondria and mitochondrial respiration was rescued in those tissues, in which the tissue pathology was alleviated.


The results of the study provide the first proof of concept that AOX bypass alleviates the pathological manifestations and expands lifespan in a relevant genetic mouse model of a human mitochondrial disorder.


Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy.

Rajendran J, Purhonen J, Tegelberg S, Smolander OP, Mörgelin M, Rozman J, Gailus-Durner V, Fuchs H, Hrabe de Angelis M, Auvinen P, Mervaala E, Jacobs HT, Szibor M, Fellman V, Kallijärvi J

EMBO Mol Med. 2019 Jan;11(1). pii: e9456. doi: 10.15252/emmm.201809456.


Sea squirt alternative oxidase bypasses fatal mitochondrial heart disease

Ann Saada, EMBO Mol Med (2019) 11:e9962DOI 10.15252/emmm.201809962