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The various roles of the mitochondria and the microbiome in health and disease have been thoroughly investigated, though they are often examined independently and in the context of chronic disease. However, the mitochondria and microbiome are closely connected, namely, through their evolution, maternal inheritance patterns, overlapping role in many diseases and their importance in the maintenance of human health. The concept known as the \"mitochondria-microbiome crosstalk\" is the ongoing bidirectional crosstalk between these two entities and warrants further exploration and consideration, especially in the context of primary mitochondrial disease, where mitochondrial dysfunction can be detrimental for clinical manifestation of disease, and the role and composition of the microbiome is rarely investigated. A potential mechanism underlying this crosstalk is the role of metabolites from both the mitochondria and the microbiome. During digestion, gut microbes modulate compounds found in food, which can produce metabolites with various bioactive effects. Similarly, mitochondrial metabolites are produced from substrates that undergo biochemical processes during cellular respiration. This review aims to provide an overview of current literature examining the mitochondria-microbiome crosstalk, the role of commonly studied metabolites serve in signaling and mediating these biochemical pathways, and the impact diet has on both the mitochondria and the microbiome. As a final point, this review highlights the up-to-date implications of the mitochondria-microbiome crosstalk in mitochondrial disease and its potential as a therapeutic tool or target.

BACKGROUND: This study aimed to explore the demographic characteristics, diagnostic challenges, treatment patterns, and caregiver burden of mitochondrial diseases.
METHODS: This retrospective cross-sectional study enrolled patients diagnosed with mitochondrial diseases from the Department of Neurology at Peking University First Hospital between January 2010 and December 2021. A questionnaire covering demographic characteristics, diagnostic dilemma, treatment, economic aspects, and caregiver stress was administered, and disability was assessed using the modified Rankin Scale (mRS).
RESULTS: A total of 183 patients (mean age: 16 (IQR: 12-25), 49.72% males) were enrolled, including 124 pediatric patients and 59 adult patients. MELAS (106. 57.92%) and Leigh syndrome (37, 20.22%) were predominant among the mitochondrial disease subtypes. Among them, 132 (72.13%) patients were initially misdiagnosed with other diseases, 58 (31.69%) patients visited 2 hospitals before confirmed as mitochondrial disease, and 39 (21.31%) patients visited 3 hospitals before confirmed as mitochondrial disease. Metabolic modifiers were the most common type of drugs used, including several dietary supplements such as L-carnitine (117, 63.93%), Coenzyme Q10 (102, 55.74%), idebenone (82, 44.81%), and vitamins (99, 54.10%) for proper mitochondrial function. Mothers are the primary caregivers for both children (36.29%) and adults (38.98%). The mRS score ranged from 0 to 5, 92.35% of the patients had different degrees of disability due to mitochondrial disease. The average monthly treatment cost was 3000 RMB for children and 3100 RMB for adults.
CONCLUSIONS: This study provided valuable insights into the characteristics and challenges of mitochondrial diseases, which underscores the need for improved awareness, diagnostic efficiency, and comprehensive support for patients and caregivers.

Mitochondrial cytopathies can have kidney involvement in up to half of cases. Their diagnosis is challenging due to phenotypic variability, lack of noninvasive tests to assess mitochondrial dysfunction and genetic heterogeneity. We report on a young adult male with hypertrophic cardiomyopathy (HCM) and chronic kidney disease (CKD) with sub-nephrotic proteinuria, who presented to the emergency department with kidney failure and hypervolemia requiring dialysis. A kidney biopsy showed focal segmental and global glomerulosclerosis, extensive foot process effacement, and abnormal mitochondria in podocytes and tubular epithelial cells; the genetic workup identified a rare FASTKD2 exon 2 variant, c.29G>C p.(Ser10Thr), in homozygosity; and functional mitochondrial assays in cultured skin fibroblasts showed reduction in FASTKD2 protein expression and moderate combined impairment in mitochondrial respiratory chain (MRC) assembly and function. This is the first report of a FASTKD2-associated cardiorenal mitochondrial cytopathy, characterized by young adult-onset proteinuric CKD and dilated HCM, in the absence of the severe neurologic manifestations described in patients with biallelic FASTKD2 mutations. We hypothesize that the increased production of reactive oxygen species associated with moderate MRC impairment could result in a smoldering podocytopathy with progressive proteinuric CKD, without overt tubulopathy or encephalomyopathy, which are, instead, pathogenically related to adenosine triphosphate deficiency.

OBJECTIVE: Deoxyguanosine kinase deficiency is one genetic cause of mtDNA depletion syndrome. Its major phenotypes include neonatal/infantile-onset hepatocerebral disease, isolated hepatic disease and myopathic disease. In this retrospective study, we seek to describe the natural history of deoxyguanosine kinase deficiency and identify any genotype-phenotype correlations.
METHODS: Retrospective literature search and collation of data from genetically confirmed cases of deoxyguanosine kinase deficiency.
RESULTS: 173 cases of DGUOK deficiency were identified. Neonatal/infantile-onset hepatocerebral disease accounted for 128 (74%) of cases. Isolated liver disease was seen in 36 (21%) and myopathic disease in 9 (5%) of cases. The most frequently involved systems were liver (98%), brain (75%), growth (46%) and gastrointestinal tract (26%). Infantile-onset disease typically presented with cholestatic jaundice and lactic acidosis. Neurological involvement included hypotonia, nystagmus and developmental delay with MRI brain abnormalities in about half of cases. Missense variants accounted for 48% of all pathogenic variants while variants resulting in truncated transcripts accounted for 39%. Prognosis was poor, especially for neonatal/ infantile-onset hepatocerebral disease for which 1 year survival was 11%. Twenty-three patients received liver transplants, of whom 12 died within 2 years of transplant. Patients with two truncating variants had a higher risk of death and were more likely to have the neonatal/infantile-onset hepatocerebral disease phenotype. No blood biomarker predictive of neurological involvement was identified. Earlier onset correlated with increased mortality.
CONCLUSIONS: There is a narrow window for therapeutic intervention. For the hepatocerebral disease phenotype, median age of onset was 1 month while the median age of death was 6.5 months implying rapid disease progression.

Aminoacyl-tRNA synthetases are essential enzymes for the accurate translation of genetic information. IARS1 and IARS2 are isoleucyl-tRNA synthetases functioning in the cytoplasm and mitochondria, respectively, with genetic mutations in these enzymes causing diverse clinical phenotypes in specific organs and tissues. Mutations in IARS1 and IARS2 have recently been linked to mitochondrial diseases. This review aims to explore the relationship between IARS1 and IARS2 and these diseases, providing a comprehensive overview of their association with mitochondrial diseases. Mutations in IARS1 cause weak calf syndrome in cattle and mitochondrial diseases in humans, leading to growth retardation and liver dysfunction. Mutations in IARS2 are associated with Leigh syndrome, craniosynostosis and abnormal genitalia syndrome. Future research is expected to involve genetic analysis of a larger number of patients, identifying new mutations in IARS1 and IARS2, and elucidating their impact on mitochondrial function. Additionally, genetically modified mice and the corresponding phenotypic analysis will serve as powerful tools for understanding the functions of these gene products and unraveling disease mechanisms. This will likely promote the development of new therapies and preventive measures.

Pyruvate dehydrogenase complex deficiency (PDCD) is a mitochondrial disorder of carbohydrate oxidation characterized by lactic acidosis and central nervous system involvement. Knowledge of the affected metabolic pathways and clinical observations suggest that early initiation of the ketogenic diet may ameliorate the metabolic and neurologic course of the disease. We present a case in which first trimester ultrasound identified structural brain abnormalities prompting a prenatal molecular diagnosis of PDCD. Ketogenic diet, thiamine, and N-acetylcysteine were initiated in the perinatal period with good response, including sustained developmental progress. This case highlights the importance of a robust neurometabolic differential diagnosis for prenatally diagnosed structural anomalies and the use of prenatal molecular testing to facilitate rapid, genetically tailored intervention.

UNASSIGNED: To study the effectiveness of liver transplantation (LT) in treating mitochondrial DNA depletion syndrome (MDS) caused by the MPV17 gene variant.
UNASSIGNED: A boy aged 2.8 years presented with edema of the lower limbs and abdomen, which persisted for over 10 days and was of unknown origin; this was accompanied by abnormal liver function, intractable hypoglycemia, and hyperlactatemia. During the second week of onset, he developed acute-on-chronic liver failure and was diagnosed with MDS due to homozygous variant c.293C>T in the MPV17 gene. Subsequently, he underwent LT from a cadaveric donor. At follow-up after 15 months, his liver function was found to be normal, without any symptoms. Additionally, a literature review was performed that included MDS patients with the MPV17 variant who underwent LT. The results demonstrated that the survival rates for MDS patients who underwent LT were 69.5%, 38.6%, 38.6%, and 38.6% at 1-year, 5-year, 10-year, and 20-year intervals, respectively. Sub-group analyses revealed the survival rate of MDS patients with isolated liver disease (83.33%, 5/6) was higher than that of hepatocerebral MDS patients (44.44%, 8/18). Fifteen variants were identified in the MPV17 gene, and patients with the c.293C>T (p.P98l) variant exhibited the highest survival rate.
UNASSIGNED: Hepatocerebral MDS patients without neurological symptoms may benefit from LT.

Mitochondrial disorders are a group of clinically and biochemically heterogeneous genetic diseases within the group of inborn errors of metabolism. Primary mitochondrial diseases are mainly caused by defects in one or several components of the oxidative phosphorylation system (complexes I-V). Within these disorders, those associated with complex III deficiencies are the least common. However, thanks to a deeper knowledge about complex III biogenesis, improved clinical diagnosis and the implementation of next-generation sequencing techniques, the number of pathological variants identified in nuclear genes causing complex III deficiency has expanded significantly. This updated review summarizes the current knowledge concerning the genetic basis of complex III deficiency, and the main clinical features associated with these conditions.

BACKGROUND: The aim of this study was to create a molecular diagnostic platform and establish a diagnostic pipeline for patients highly suspected of mitochondrial disorders. The effectiveness of three methods, namely, traditional restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR), Sanger sequencing for hotspot detection and whole mitochondrial DNA (mtDNA), and third-generation (Nanopore) whole mtDNA sequencing, will be compared in diagnosing patients with suspected primary mitochondrial diseases (PMDs). The strengths and limitations of different methods are also discussed.
METHODS: A single-center prospective cohort study was conducted to validate the diagnostic pipeline for suspected mitochondrial diseases. In the first stage, a PCR-based method with five sets of primers was used to screen for eight hotspots (m.3243A>G, m.3460G>A, m.8344A>G, m.8993T>G, m.9185T>C, m.11778G>A, m.13513G>A, and m.4977deletion) using either RFLP or direct Sanger sequencing. Sanger sequencing was also used to confirm the RFLP-positive samples. In the second stage, for samples with negative screening results for the eight hotspots, mitochondrial whole-genome sequencing was performed using Sanger sequencing or third-generation nanopore sequencing.
RESULTS: Between June 2020 and May 2023, 30 patients from ages 0 to 63 with clinically suspected mitochondrial disease were enrolled. The positive yield for the diagnosis of PMDs was 8/30=26.7%, and the sensitivity of the heteroplasmy level for the RFLP-based method was approximately 5%. The remaining 22 patients who tested negative at the first stage were tested using Sanger sequencing or the third-generation sequencing Nanopore, and all tested negative for pathological mtDNA mutations. Compared to the Sanger sequencing method, the results of RFLP-PCR were compromised by the limitations of incomplete RFLP enzyme digestion. For whole-genome sequencing of mtDNA, Sanger sequencing, instead of nanopore sequencing, is preferred at our institution because of its cost-effectiveness.
CONCLUSIONS: In our highly selective cohort, most tested positive in the first stage of the 8 hot spots screen. Sanger sequencing is a conventional and accurate method for mitochondrial disease screening, at least for the most common hot spots in the region. The results revealed that Sanger sequencing is an accurate method with the benefit of being more cost-effective. This integral platform of molecular diagnosis bears the advantages of being relatively low cost and having a shorter reporting time, facilitating crucial identification of patients with clinical evidence of such disorders. This diagnostic flowchart has also been translated into routine clinical use in the tertiary hospital.