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New Avenues of Heme Synthesis Regulation.

ABSTRACT: During erythropoiesis, there is an enormous demand for the synthesis of the essential cofactor of hemoglobin, heme. Heme is synthesized de novo via an eight enzyme-catalyzed pathway within each developing erythroid cell. A large body of data exists to explain the transcriptional regulation of the heme biosynthesis enzymes, but until recently much less was known about alternate forms of regulation that would allow the massive production of heme without depleting cellular metabolites. Herein, we review new studies focused on the regulation of heme synthesis via carbon flux for porphyrin synthesis to post-translations modifications (PTMs) that regulate individual enzymes. These PTMs include cofactor regulation, phosphorylation, succinylation, and glutathionylation. Additionally discussed is the role of the immunometabolite itaconate and its connection to heme synthesis and the anemia of chronic disease. These recent studies provide new avenues to regulate heme synthesis for the treatment of diseases including anemias and porphyrias.

SUBMITTER: Medlock AE

PROVIDER: S-EPMC9267699 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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New Avenues of Heme Synthesis Regulation.

Medlock Amy E AE Dailey Harry A HA

International journal of molecular sciences 20220705 13

During erythropoiesis, there is an enormous demand for the synthesis of the essential cofactor of hemoglobin, heme. Heme is synthesized de novo via an eight enzyme-catalyzed pathway within each developing erythroid cell. A large body of data exists to explain the transcriptional regulation of the heme biosynthesis enzymes, but until recently much less was known about alternate forms of regulation that would allow the massive production of heme without depleting cellular metabolites. Herein, we r ...[more]

PMID: 35806474

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Project description:Mitochondrial optic neuropathies are a group of optic nerve atrophies exemplified by the two commonest conditions in this group, autosomal dominant optic atrophy (ADOA) and Leber's hereditary optic neuropathy (LHON). Their clinical features comprise reduced visual acuity, colour vision deficits, centro-caecal scotomas and optic disc pallor with thinning of the retinal nerve fibre layer. The primary aetiology is genetic, with underlying nuclear or mitochondrial gene mutations. The primary pathology is owing to retinal ganglion cell dysfunction and degeneration. There is currently only one approved treatment and no curative therapy is available. In this review we summarise the genetic and clinical features of ADOA and LHON and then examine what new avenues there may be for therapeutic intervention. The therapeutic strategies to manage LHON and ADOA can be split into four categories: prevention, compensation, replacement and repair. Prevention is technically an option by modifying risk factors such as smoking cessation, or by utilising pre-implantation genetic diagnosis, although this is unlikely to be applied in mitochondrial optic neuropathies due to the non-life threatening and variable nature of these conditions. Compensation involves pharmacological interventions that ameliorate the mitochondrial dysfunction at a cellular and tissue level. Replacement and repair are exciting new emerging areas. Clinical trials, both published and underway, in this area are likely to reveal future potential benefits, since new therapies are desperately needed.Plain language summaryOptic nerve damage leading to loss of vision can be caused by a variety of insults. One group of conditions leading to optic nerve damage is caused by defects in genes that are essential for cells to make energy in small organelles called mitochondria. These conditions are known as mitochondrial optic neuropathies and two predominant examples are called autosomal dominant optic atrophy and Leber's hereditary optic neuropathy. Both conditions are caused by problems with the energy powerhouse of cells: mitochondria. The cells that are most vulnerable to this mitochondrial malfunction are called retinal ganglion cells, otherwise collectively known as the optic nerve, and they take the electrical impulse from the retina in the eye to the brain. The malfunction leads to death of some of the optic nerve cells, the degree of vision loss being linked to the number of those cells which are impacted in this way. Patients will lose visual acuity and colour vision and develop a central blind spot in their field of vision. There is currently no cure and very few treatment options. New treatments are desperately needed for patients affected by these devastating diseases. New treatments can potentially arise in four ways: prevention, compensation, replacement and repair of the defects. Here we explore how present and possible future treatments might provide hope for those suffering from these conditions.

Dataset Information

New Avenues of Heme Synthesis Regulation.

Publications

New Avenues of Heme Synthesis Regulation.

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