Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria

Abstract

Acute intermittent porphyria (AIP) is an autosomal dominant inborn error of heme biosynthesis due to a pathogenic mutation in the Hmbs gene, resulting in half-normal activity of hydroxymethylbilane synthase. Factors that induce hepatic heme biosynthesis induce episodic attacks in heterozygous patients. The clinical presentation of acute attacks involves the signature neurovisceral pain and may include psychiatric symptoms. Here we used a knock-in mouse line that is biallelic for the Hmbs c.500G > A (p.R167Q) mutation with~5% of normal hydroxymethylbilane synthase activity to unravel the consequences of severe HMBS deficiency on affective behavior and brain physiology. Hmbs knock-in mice (KI mice) model the rare homozygous dominant form of AIP and were used as tool to elucidate the hitherto unknown pathophysiology of the behavioral manifestations of the disease and its neural underpinnings. Extensive behavioral analyses revealed a selective depression-like phenotype in Hmbs KI mice; transcriptomic and immunohistochemical analyses demonstrated aberrant myelination. The uncovered compromised mitochondrial function in the hippocampus of knock-in mice and its ensuing neurogenic and neuroplastic deficits lead us to propose a mechanistic role for disrupted mitochondrial energy production in the pathogenesis of the behavioral consequences of severe HMBS deficiency and its neuropathological sequelae in the brain.

α-Lipoic Acid Improves Hepatic Metabolic Dysfunctions in Acute Intermittent Porphyria: A Proof-of-Concept Study

“…Homedan et al showed that hepatic complexes I, II, and III, but not complex IV, decreased their activities in PBGD -deficient mice treated with phenobarbital, which is a drug that induces the acute episodes [ 11 , 28 ]. Conversely, the morphological alterations of mitochondria presenting paracristallin inclusions have been described in the liver biopsies of AIP patients [ 29 ], and a lack of complex IV activity alongside the collapse of ATP was found in the hippocampus of AIP mice knocked-in for the Hmbs c.500G > A (p.R167Q) mutation, resulting in a severe phenotype with neuropsychiatric behavior [ 30 ]. Most recently, it has been demonstrated that the deficiency of ferrochelatase ( FETCH ), a gene involved in the last step of heme production and responsible for the development of Erythropoietic protoporphyria, damaged both glycolysis and OXPHOS along with a decrease in mitochondrial fusion [ 31 ].…”

“…Most recently, it has been demonstrated that the deficiency of ferrochelatase ( FETCH ), a gene involved in the last step of heme production and responsible for the development of Erythropoietic protoporphyria, damaged both glycolysis and OXPHOS along with a decrease in mitochondrial fusion [ 31 ]. Still, glucose metabolism and mitochondrial dysfunction might precipitate the acute attacks, but not all studies share the same alterations, possibly reflecting the huge phenotypic variability of AIP symptomatology [ 11 , 28 , 29 , 30 , 31 ]. Overall, our model may support the hypothesis that fasting on one hand worsens glycolytic alterations and on the other unmasks mitochondrial damage by shifting mitochondrial dynamics toward fission rather than fusion and, consequently, contributing to OXPHOS aberrancies.…”

The α-Lipoic Acid Improves Hepatic Metabolic Dysfunctions in Acute Intermittent Porphyria: A Proof-of-Concept Study

“…Homedan et al showed that hepatic complexes I, II and III, but not complex IV, decreased their activities in PBGD-deficient mice treated with phenobarbital, a drug which induces the acute episodes [12,29]. Conversely, morphological alterations of mitochondria presenting para-crystallin inclusions have been described in liver biopsies of AIP patients [30] and lack of complex IV activity alongside collapse of ATP were found in the hippocampus of AIP mice knocked-in for the Hmbs c.500G > A (p.R167Q) mutation, resulting in a severe phenotype with neuropsychiatric behavior [31]. Most recently, it has been demonstrated that the deficiency of ferrochelatase (FETCH), a gene involved in the last step of heme production and responsible for the development of Erythropoietic protoporphyria, damaged both glycolysis and OXPHOS along with a decrease in mitochondrial fusion [32].…”

“…Most recently, it has been demonstrated that the deficiency of ferrochelatase (FETCH), a gene involved in the last step of heme production and responsible for the development of Erythropoietic protoporphyria, damaged both glycolysis and OXPHOS along with a decrease in mitochondrial fusion [32]. Still, glucose metabolism and mitochondrial dysfunction might precipitate the acute attacks but not all studies share the same alterations possibly reflecting the huge phenotypic variability of AIP symptomatology [12,[29][30][31][32]. Overall, our model may support the hypothesis that fasting on one hand worsens glycolytic alterations and on the other unmasks mitochondrial damage by shifting mitochondrial dynamics towards fission rather than fusion and, consequently, contributing to OXPHOS aberrancies.…”

Cutting-Edge Therapies and Novel Strategies for Acute Intermittent Porphyria: Step-by-Step towards the Solution

“…In addition, HMBS deficiency in a knock-inmouse model that was biallelic for the Hmbs c.500G > A (p.R167Q) mutation significantly decreased the enzymatic activity of complexes III and IV in the hippocampus, mainly due to the reduction in heme availability. Consequently, the lower respiration capacity reduced the mitochondrial membrane potential, leading to higher ATP consumption rather than production [54].…”