Clinical profile and outcome of cardiac involvement in MELAS syndrome

Brambilla, Alice; Favilli, Silvia; Olivotto, Iacopo; Calabri, G; Porcedda, Giulio; Simone, Luciano; Procopio, Elena; Pasquini, Elisabetta

doi:10.1016/j.ijcard.2018.10.051

Cited by 25 publications

(19 citation statements)

References 15 publications

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“…Compared to 143BTK− ρ0 cells with abolished respiration, 143BTK− ρ0 + HEK293T hybrid cells showed an improved respiratory profile. In contrast, 143BTK− ρ0 + MELAS hybrid cells recapitulated the impaired respiratory profile observed for MELAS patient-derived cells 12,42 . Additionally, we performed qPCR on 143BTK− ρ0 cells containing either MELAS or wild type (WT) transferred mitochondria to compare the restored mtDNA levels to unmodified 143BTK− parental cells ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 82%

“…One in 5,000 people have some degree of a pathological mtDNA disorder, and up to 1 in 8 individuals carry low levels of a mtDNA mutation that can be inherited through the maternal germline 8 – 11 . Mitochondrial replacement therapy (MRT) aims to prevent transmission of mtDNA disorders from affected mothers to offspring, but limited treatments exist for those already living with a pathological mtDNA mutation 12 , 13 .…”

Section: Introductionmentioning

confidence: 99%

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Stable retention of chloramphenicol-resistant mtDNA to rescue metabolically impaired cells

Dawson

Patananan

Sercel

et al. 2020

Sci Rep

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The permanent transfer of specific mtDNA sequences into mammalian cells could generate improved models of mtDNA disease and support future cell-based therapies. Previous studies documented multiple biochemical changes in recipient cells shortly after mtDNA transfer, but the long-term retention and function of transferred mtDNA remains unknown. Here, we evaluate mtDNA retention in new host cells using 'MitoPunch', a device that transfers isolated mitochondria into mouse and human cells. We show that newly introduced mtDNA is stably retained in mtDNA-deficient (ρ0) recipient cells following uridine-free selection, although exogenous mtDNA is lost from metabolically impaired, mtDNA-intact (ρ+) cells. We then introduced a second selective pressure by transferring chloramphenicol-resistant mitochondria into chloramphenicol-sensitive, metabolically impaired ρ+ mouse cybrid cells. Following double selection, recipient cells with mismatched nuclear (nDNA) and mitochondrial (mtDNA) genomes retained transferred mtDNA, which replaced the endogenous mutant mtDNA and improved cell respiration. However, recipient cells with matched mtDNA-nDNA failed to retain transferred mtDNA and sustained impaired respiration. Our results suggest that exogenous mtDNA retention in metabolically impaired ρ+ recipients depends on the degree of recipient mtDNA-nDNA co-evolution. Uncovering factors that stabilize exogenous mtDNA integration will improve our understanding of in vivo mitochondrial transfer and the interplay between mitochondrial and nuclear genomes. Mutations in the multi-copy mitochondrial genome (mtDNA) can impair the biosynthesis of ATP, metabolites, fatty acids, reactive oxygen species, and iron sulfur clusters 1-4. Even a single nucleotide polymorphism can have profound effects on cellular function and contribute to pathologies including cardiomyopathies, diabetes, autoimmune diseases, neurological disorders, cancer, and even aging 5,6. The degree of pathology often depends on the ratio of mutant to wild-type mtDNA populations within the same cell, a situation known as heteroplasmy 7. One in 5,000 people have some degree of a pathological mtDNA disorder, and up to 1 in 8 individuals carry low levels of a mtDNA mutation that can be inherited through the maternal germline 8-11. Mitochondrial replacement therapy (MRT) aims to prevent transmission of mtDNA disorders from affected mothers to offspring, but limited treatments exist for those already living with a pathological mtDNA mutation 12,13. Our ability to repair mutant mtDNA and improve metabolically impaired cells would advance disease modeling studies and potential cell-based therapies for mtDNA disorders. Gene therapy and now gene editing is a viable treatment option for some nucleus-encoded disorders 5,14,15. In contrast, specific mtDNA mutations are difficult to generate or repair because current gene modifying approaches do not work well inside mitochondria.

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Section: Resultsmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Stable retention of chloramphenicol-resistant mtDNA to rescue metabolically impaired cells

Dawson

Patananan

Sercel

et al. 2020

Sci Rep

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“…However, in other settings such as MELAS syndrome [ 8 ], patients presenting with CVI were globally more compromised, and heart disease seemed to represent a hallmark of phenotype severity rather than the primary cause of demise. This paradigm also seems to apply to TMEM70 deficiency, in which heart involvement is a constant feature but per se a stable one; acute decompensation may develop as consequence of metabolic crisis or severe infections [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…Eight patients with paediatric onset Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome from the present cohort have been included in a recent publication addressing cardiac phenotypes [ 8 ] Four patients diagnosed by whole exome sequencing have been described as isolated case reports [ 9 – 11 ].…”

Section: Methodsmentioning

confidence: 99%

Impact of cardiovascular involvement on the clinical course of paediatric mitochondrial disorders

Brambilla

Olivotto

Favilli

et al. 2020

Orphanet J Rare Dis

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Background Primary mitochondrial disorders (PMD) are rare conditions resulting in progressive multi-organ failure. Cardiovascular involvement (CVI) has been reported in paediatric patients. However, its age-related prevalence, clinical presentation and prognostic impact are unresolved. We detailed CVI in a cohort of children diagnosed with PMD over two decades at a tertiary referral centre. Results We enrolled 86 PMD patients (M/F = 30/56; mean age 6.4 ± 8.58 years). CVI was detected in 31 patients (36%), with mean age at onset of 5.7 ± 7.8 years including the pre- and neonatal phase in 14, often representing the first sign of PMD (42% of those with CVI). Heart disease resulted more common in males and in children with specific aetiologies (Barth, TMEM70 and MELAS syndromes). Hypertrophic, non-compaction and dilated cardiomyopathies were the prevalent disorders, although pulmonary arterial hypertension was also found. Adverse cardiac events (heart failure, resuscitated cardiac arrest, ICD/PM implantation, sudden death) occurred in 19% of children with CVI over a follow-up period of 5.4 ± 4.3 years. All-cause mortality was higher in patients with CVI compared to those without CVI (45.1% vs 21.8%; p < 0.01); female sex, age at onset < 5 years, acute heart failure at presentation and diabetes also proved independent predictors of outcome. Conclusion Cardiovascular involvement occurred in over one-third of children diagnosed with PMD, often at a very early age, and was associated with adverse prognosis. Final outcome of PMD-related CVI was influenced by the specific underlying aetiology, suggesting the need for tailored management of heart failure and sudden death prevention.

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“…W grupie 113 pediatrycznych pacjentów z MD przeżywalność do 16. roku życia u dzieci z kardiomiopatią i bez niej wynosiła odpowiednio 18% i 95% [33]. Wydaje się, że kardiomiopatia u dorosłych przebiega łagodniej i lepiej rokuje [6,22]. W 7-letniej obserwacji 260 pacjentów u 10% z nich wystąpił punkt końcowy (nagły zgon, zgon z powodu HF, zresuscytowane zatrzymanie krążenia, blok AV III°, dysfunkcja węzła zatokowego, transplantacja serca lub hospitalizacja z powodu HF).…”

Section: Rokowanie I Naturalny Przebieg Chorobyunclassified