DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass.

Mitochondrial quality control is essential in highly structured cells such as neurons and muscles. In skeletal muscle the mitochondrial fission proteins are reduced in different physiopathological conditions including ageing sarcopenia, cancer cachexia and chemotherapy-induced muscle wasting. However, whether mitochondrial fission is essential for muscle homeostasis is still unclear. Here we show that muscle-specific loss of the pro-fission dynamin related protein (DRP) 1 induces muscle wasting and weakness. Constitutive Drp1 ablation in muscles reduces growth and causes animal death while inducible deletion results in atrophy and degeneration. Drp1 deficient mitochondria are morphologically bigger and functionally abnormal. The dysfunctional mitochondria signals to the nucleus to induce the ubiquitin-proteasome system and an Unfolded Protein Response while the change of mitochondrial volume results in an increase of mitochondrial Ca2+ uptake and myofiber death. Our findings reveal that morphology of mitochondrial network is critical for several biological processes that control nuclear programs and Ca2+ handling.

The phenotypic spectrum of fifty Czech m.3243A>G carriers.

BACKGROUND: Mitochondrial myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes syndrome (MELAS) is a common mitochondrial disorder with varying multisystemic clinical manifestation. We present a comprehensive clinical picture of 50 Czech m.3243A>G carriers with emphasis on the sequence of symptoms in symptomatic patients. RESULTS: Symptoms developed in 33 patients (66%) and 17 carriers remained unaffected (34%). The age of onset varied from 1month to 47years of age, with juvenile presentation occurring in 53% of patients. Myopathy was the most common presenting symptom (18%), followed by CPEO/ptosis and hearing loss, with the latter also being the most common second symptom. Stroke-like episodes (SLE) occurred in fourteen patients, although never as a first symptom, and were frequently preceded by migraines (58%). Rhabdomyolysis developed in two patients. The second symptom appeared 5.0±8.3years (range 0-28years) after the first, and the interval between the second and third symptom was 2.0±6.0years (range 0-21years). Four of our patients remained monosymptomatic up to 12years of follow-up. The sequence of symptoms according to their time of manifestation was migraines, myopathy, seizures, CPEO/ptosis, SLE, hearing loss, and diabetes mellitus. The average age at death was 32.4±17.7years (range 9-60years) in the juvenile form and 44.0±12.7years (range 35-53years) in the adult form. Some patients with SLE harboured very low heteroplasmy levels in various tissues. No threshold for any organ dysfunction could be determined based on these levels. CONCLUSIONS: Sufficient knowledge of the timeline of the natural course of MELAS syndrome may improve the prediction and management of symptoms in patients with this mitochondrial disease.

Earlier diagnosis and strict diets improve the survival rate and clinical course of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

AIM: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a severe metabolic disease that, without treatment, often leads to premature death or serious handicap. The aim of this study was to evaluate the clinical course of LCHADD with the homozygous 1528G>C (E510Q) mutation when patients underwent strict dietary treatment. METHODS: From 1997 to 2010, 16 patients with LCHADD were diagnosed in Finland. They were followed up, and data were prospectively collected as they emerged. Clinical data before diagnosis were retrospectively collected from hospital records. This cohort was compared with an earlier cohort of patients diagnosed from 1976 to 1996. RESULTS: The disease presented from birth to five months of age with failure to thrive, hypotonia, hepatomegaly, metabolic acidosis, cardiomyopathy and hypoketotic hypoglycaemia. In this cohort, the therapeutic delay was 0-30 days and the survival rate at the end of the study was 62.5% compared with 10-year survival rate of 14.3% for the earlier cohort. The survivors were in good overall condition, but some of them had developed mild retinopathy or mild neuropathy. CONCLUSION: Earlier diagnosis and stricter dietary regimes improved the survival rates and clinical course of patients with LCHADD in Finland. However, improvements in therapy are still needed to prevent the development of long-term complications, such as retinopathy and neuropathy.

Long-term outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases.

OBJECTIVES: We sought to determine the clinical spectrum, survival, and long-term functional outcome of a cohort of pediatric patients with mitochondrial diseases and to identify prognostic factors. METHODS: Medical charts were reviewed for 73 children diagnosed between 1985 and 2005. The functional status of living patients was assessed prospectively by using the standardized Functional Independence Measure scales. RESULTS: Patients fell into 7 phenotypic categories: neonatal-onset lactic acidosis (10%), Leigh syndrome (18%), nonspecific encephalopathy (32%), mitochondrial (encephalo)myopathy (19%), intermittent neurologic (5%), visceral (11%), and Leber hereditary optic neuropathy (5%). Age at first symptoms ranged from prenatal to 16 years (median: 7 months). Neurologic symptoms were the most common (90%). Visceral involvement was observed in 29% of the patients. A biochemical or molecular diagnosis was identified for 81% of the patients as follows: deficiency of complex IV (27%), of pyruvate dehydrogenase or complex I (25% each), of multiple complexes (13%), and of pyruvate carboxylase (5%) or complexes II+III (5%). A mitochondrial DNA mutation was found in 20% of patients. At present, 46% of patients have died (median age: 13 months), 80% of whom were <3 years of age. Multivariate analysis showed that age at first symptoms was a major independent predictor of mortality: patients with first symptoms before 6 months had a highly increased risk of mortality. Cardiac or visceral involvement and neurologic crises were not independent prognostic factors. Living patients showed a wide range of independence levels that correlated positively with age at first symptoms. Among patients aged >5 years (n = 32), 62% had Functional Independence Measure quotients of >0.75. CONCLUSIONS: Mitochondrial diseases in children span a wide range of symptoms and severities. Age at first symptoms is the strongest predictor mortality. Despite a high mortality rate in the cohort, 62% of patients aged >5 years have only mild impairment or normal functional outcome.

Long-term follow-up of neonatal mitochondrial cytopathies: a study of 57 patients.

OBJECTIVES: We sought to determine the long-term clinical and biochemical outcome of newborns with mitochondrial cytopathies (MCs) and to identify possible prognostic factors that may modify the course of these diseases. MATERIAL AND METHODS: Fifty-seven newborns with MCs were identified in a retrospective review (1983-2002). We defined 2 different outcome categories: clinical (neurologic, hepatic, myopathic, and multiorganic) and biochemical (lactate level normalization or initially normal remaining unchanged, decreased but not normalized, and persistently high). We used 2 different statistical approaches: (1) survival studies depending on the initial symptoms and lactate and enzymatic deficiencies using the Kaplan-Meier method; and (2) the same variables compared with different survival age groups and clinical and biochemical outcome categories using the chi2 test. RESULTS: Thirty-three patients died (57.8%), 12 remain alive (21%), and 12 were lost in the follow-up; 6 of them are currently older than 4 years. Most of the patients manifested multiorganic disease (64.8%) and high lactate level (77.1%) over time. Children surviving to 2.5 to 3 years of age were more likely to survive for a long period of time. Initial neurologic and hepatic presentation increased the risk to develop neurologic disease and severe persistent hyperlactacidemia, respectively. Initial severe hyperlactacidemia and combined enzyme deficiencies were significant risk factors for higher mortality and multiorganic disorders. Two patients with exclusively myopathic outcome are alive and cognitively normal at 12 years of life. CONCLUSIONS: Children with neonatal-onset MCs have very high mortality and poor prospects. However, some with life-threatening presentations may gradually improve, giving rise to less severe diseases. Those with exclusively myopathic symptoms have a better prognosis.

Lack of evidence of mitochondrial dysfunction in the offspring of HIV-infected women. Retrospective review of perinatal exposure to antiretroviral drugs in the Perinatal AIDS Collaborative Transmission Study.

A recent report suggesting mitochondrial dysfunction among eight HIV-exposed but uninfected children exposed perinatally to nucleoside reverse transcriptase inhibitors (NRTIs) prompted a review within the Perinatal AIDS Collaborative Transmission Study (PACTS). A standardized retrospective review was conducted of 118 deaths at < 5 years. Deaths were classified as unrelated to mitochondrial dysfunction (Class 1), unlikely related (Class 2), possibly related (Class 3), or likely related or proven (Class 4). Among 35 deaths recorded in HIV-uninfected or indeterminate children, none were classified in either Class 2, 3, or 4. We also reviewed signs or symptoms consistent with possible mitochondrial dysfunction among 1,954 living uninfected children. Only one child was in Class 3 and two siblings were in Class 2; none had perinatal antiretroviral drug exposure. We found no evidence indicating that uninfected infants exposed to perinatal NRTIs died of mitochondrial disorders or that living exposed children had symptoms of mitochondrial dysfunction.

Drug safety during pregnancy and in infants. Lack of mortality related to mitochondrial dysfunction among perinatally HIV-exposed children in pediatric HIV surveillance.

The objectives were to assess whether any deaths reported among perinatally exposed, uninfected, or indeterminate children were consistent with mitochondrial dysfunction, and to characterize perinatal exposure to antiretrovirals among children born in the last five years and reported to perinatal HIV surveillance. Population-based HIV/AIDS surveillance data on perinatally exposed children born in 1993 through 1998 from 32 states with HIV reporting and from a special HIV surveillance project in Los Angeles County and in 22 hospitals in New York City were used. The classifications of exposure and deaths were consistent with the investigation of deaths across all US cohorts. Deaths were ascertained from recent matches with death registries in each state. Causes of death were ascertained from death certificates, autopsy records when available, and medical records. None of the 98 deaths (1.1%) among 9067 perinatally exposed uninfected or indeterminate children born from 1993 through 1998 and reported through pediatric HIV surveillance died of conditions that were consistent with mitochondrial dysfunction. This included 679 children exposed to zidovudine (ZDV) and 3TC, 277 exposed to other antiretroviral combinations, 4512 exposed to ZDV alone, 927 with no antiretroviral exposure, and 2672 with unknown exposure--1128 of whom were born before March 1994 and were unlikely to have been exposed to ZDV. No deaths attributable to mitochondrial dysfunction were found through this evaluation of population-based HIV surveillance data. Long-term follow-up of antiretroviral-exposed children has been recommended by the Public Health Service. This evaluation highlights the contribution of population-based surveillance to the evaluation of potential toxicities associated with maternal antiretroviral use.

Lack of definitive severe mitochondrial signs and symptoms among deceased HIV-uninfected and HIV-indeterminate children < or = 5 years of age, Pediatric Spectrum of HIV Disease project (PSD), USA.

BACKGROUND: In response to recent reports of mitochondrial dysfunction in HIV-uninfected infants exposed to antiretroviral (ARV) prophylaxis, the Perinatal Safety Review Working Group reviewed deaths in five large HIV-exposed perinatal cohorts in the United States to determine if similar cases of severe mitochondrial toxicity could be detected. We describe the results of this review for the PSD cohort. METHODS: Hospitalization, clinic and death records for deceased HIV-uninfected and HIV-indeterminate children who were less than 5 years of age were reviewed. Standard definitions were used to classify HIV infection status and the likelihood that signs and symptoms were related to mitochondrial dysfunction. Children were classified as having signs and symptoms that were considered (1) unrelated, (2) unlikely, (3) consistent with, or (4) likely related to mitochondrial disease. SIDS deaths were put into a separate category. RESULTS: 8,465 of 13,125 HIV-exposed children were either HIV-uninfected or HIV-indeterminate. Among the 84 deaths in the subgroup of 8,465 children, 9 were considered in Class 2 (unlikely), 4 were considered in Class 3 (consistent with), and none were considered in Class 4 (likely). 97% of those children who received ARV prophylaxis received zidovudine alone. None of the HIV-uninfected deaths were classified in 2, 3, or 4; and only one of these was exposed to ARV prophylaxis. Among the 3 HIV-indeterminate children who were classified in 3 (consistent with), 2 had no or unknown ARV exposure before 1994 when use of ZDV prophylaxis became the standard of care. Both HIV-uninfected and HIV-indeterminate children with ARV exposure or unknown exposure had lower mortality rates than children without ARV exposure. CONCLUSION: Monoprophylaxis with ZDV was not associated with higher death rates in the cohort of 8,465 children or with any findings likely consistent with mitochondrial dysfunction among the 85 deaths. Ongoing monitoring of drug safety in large multi-site prospective cohort studies of HIV-exposed children is essential in the era of highly active antiretroviral therapy.

Age and cause of death in mitochondrial diseases.

We report on the age and the causes of death in 16 patients with mitochondrial diseases. Nine patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) died at a mean age of 34 years and three patients with chronic progressive external ophthalmoplegia at a mean age of 56 years. The causes of death were cardiopulmonary failure (n = 5), status epilepticus (n = 4), aspiration pneumonia (n = 2), pulmonary embolism (n = 2), renal failure (n = 1), metabolic disturbance (n = 1), and unknown causes (n = 1). Thus, many patients in this series died of medical complications, some of which may be prevented.

Mitochondrial DNA depletion in a patient with long survival.

We studied a 29-year-old woman with myopathy since childhood with evidence of mitochondrial DNA (mtDNA) depletion. Muscle biopsy sample showed cytochrome c oxidase (COX)-negative fibers. Biochemistry showed COX deficiency. Southern blot analysis showed 76% depletion of mtDNA as compared with controls. This patient's clinical course suggests that long survival is possible in some patients with mtDNA depletion.