Mitochondrial diseases caused by toxic compound accumulation: from etiopathology to therapeutic approaches

Abstract

Mitochondrial disorders are a group of highly invalidating human conditions for which effective treatment is currently unavailable and characterized by faulty energy supply due to defective oxidative phosphorylation (OXPHOS). Given the complexity of mitochondrial genetics and biochemistry, mitochondrial inherited diseases may present with a vast range of symptoms, organ involvement, severity, age of onset, and outcome. Despite the wide spectrum of clinical signs and biochemical underpinnings of this group of dis-orders, some common traits can be identified, based on both pathogenic mechanisms and potential therapeutic approaches. Here, we will review two peculiar mitochondrial disorders, ethylmalonic encephalopathy (EE) and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), caused by mutations in the ETHE1 and TYMP nuclear genes, respectively. ETHE1 encodes for a mitochondrial enzyme involved in sulfide detoxification and TYMP for a cytosolic enzyme involved in the thymidine/deoxyuridine catabolic pathway. We will discuss these two clinical entities as a paradigm of mitochondrial diseases caused by the accumulation of compounds normally present in traces, which exerts a toxic and inhibitory effect on the OXPHOS system.

Keywords: OXPHOS; mitochondrial diseases; sulfide catabolism; therapeutic approaches; thymidine/deoxyuridine catabolism.

Figure 1. Endogenous sulfide metabolism

H₂S is produced endogenously from cysteine by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), cysteine aminotransferase (CAT), and 3-mercaptopyruvate sulfurtransferase (3-MST), or exogenously by gut anaerobic bacterial flora metabolism. In mitochondria, it is initially fixed by a sulfide quinone oxidoreductase (SQR). A sulfur dioxygenase (SDO/ETHE1) oxidizes the persulfide to sulfite (H₂SO₃) in a reaction that includes molecular oxygen and water. See text for details. SUOX, sulfite oxidase; TST, thiosulfate sulfur transferase; cIII, complex III; cIV, complex IV.

Figure 2. H₂S in health and disease

Physiological (green bordered) and toxic (red bordered) effects of H₂S in mammal tissues and organs. See text for details.

Figure 3. Summarized pyrimidines metabolism

Interconnections between biosynthetic (de novo synthesis, blue bordered), catabolic (degradation, red bordered), and recycling (salvage, green bordered) pyrimidine pathways in mammalian cells. See text for details.

Figure 4. Deoxynucleotide pool imbalance in MNGIE

Loss of thymidine phosphorylase (TP) activity causes toxic accumulation of deoxythymidine and deoxyuridine nucleosides and dNTP pool imbalances, which impair mtDNA replication causing depletion, multiple deletions, and point mutations.