Therapy Prospects for Mitochondrial DNA Maintenance Disorders

Abstract

Mitochondrial DNA depletion and multiple deletions syndromes (MDDS) constitute a group of mitochondrial diseases defined by dysfunctional mitochondrial DNA (mtDNA) replication and maintenance. As is the case for many other mitochondrial diseases, the options for the treatment of these disorders are rather limited today. Some aggressive treatments such as liver transplantation or allogeneic stem cell transplantation are among the few available options for patients with some forms of MDDS. However, in recent years, significant advances in our knowledge of the biochemical pathomechanisms accounting for dysfunctional mtDNA replication have been achieved, which has opened new prospects for the treatment of these often fatal diseases. Current strategies under investigation to treat MDDS range from small molecule substrate enhancement approaches to more complex treatments, such as lentiviral or adenoassociated vector-mediated gene therapy. Some of these experimental therapies have already reached the clinical phase with very promising results, however, they are hampered by the fact that these are all rare disorders and so the patient recruitment potential for clinical trials is very limited.

Keywords: depletion; gene therapy; mitochondria; mtDNA; multiple deletions; nucleoside; replication; therapy.

Figure 1

Metabolic pathways and proteins involved in mitochondrial DNA replication disorders. Proteins whose mutations have been linked to MDDS are depicted in yellow (mtDNA replication/maintenance machinery), dark blue (dNTP metabolism), red (mitochondrial dynamics) and green (unknown role in mtDNA replication). Light blue colour represents proteins participating in dNTP metabolism but not associated with MDDS. Abbreviations: ABAT, 4-aminobutyrate aminotransferase; AFG3L2, AFG3-like protein 2; AGK, acylglycerol kinase; ANT1, adenine nucleotide translocator 1; CDA, cytidine deaminase; cdN, cytosolic deoxyribonucleotidase; C1QBP, complement component 1 Q subcomponent-binding protein; dAdo, deoxyadenosine; dCK, deoxycytidine kinase; dCtd, deoxycytidine; dCTD, deoxycytidylate deaminase; dGK, deoxyguanosine kinase; dGuo, deoxyguanosine; DNA2, helicase/nuclease DNA2; dThd, thymidine; dUrd, deoxyuridine; ENT1, equilibrative nucleoside transporter 1; FBXL4, F-box/LRR-repeat protein 4; GFER, growth factor, augmenter of liver regeneration; LIG3, ligase III; mdN, mitochondrial deoxyribonucleotidase; MFN2, mitofusin 2; MGME1, mitochondrial genome maintenance exonuclease 1; MICOS13, MICOS complex subunit MIC13; MPV17, protein MPV17; MRM2, rRNA methyltransferase 2; MSTO1, protein misato homolog 1; NDPK, nucleoside diphosphate kinase; NMPK, nucleoside monophosphate kinase; OPA1, dynamin-like 120 kDa protein; POLG1, catalytic subunit of polymerase gamma; POLG2, ancillary subunit of polymerase gamma; p53R2; p53-inducible small subunit of the ribonucleotide reductase; R2, small subunit of the ribonucleotide reductase; RNASEH1, ribonuclease H1; RNR, ribonucleotide reductase; SLC25A10, mitochondrial dicarboxylate carrier; SLC25A21, mitochondrial 2-oxodicarboxylate carrier; SPG7, paraplegin; SSBP1, mitochondrial single strand binding protein; SUCLA2, β-subunit of the succinate-CoA ligase; SUCLG1, α-subunit of the succinate-CoA ligase; TFAM, mitochondrial transcription factor 1; TK1, thymidine kinase 1; TK2, thymidine kinase 2; TOP3A, DNA topoisomerase 3 alpha; TP, thymidine phosphorylase; TS, thymidylate synthase; Twinkle, mitochondrial helicase. Right bottom corner: the 2 isoforms of tetrameric RNR are represented, 2R1/2R2 (active in proliferating cells) and 2R1/2p53R2 (active throughout the cell cycle). Question marks indicate that the mitochondrial transporter(s) of the deoxyribonucleoside mono-, di- and triphosphates has or have not been identified. Figure generated using the Adobe^® Photoshop^® CS5 software.