About

Marni Joy Falk, MD, is a Professor of Pediatrics (Human Genetics) at the Children's Hospital of Philadelphia. She serves as an Attending Physician in the Divisions of Human Genetics and Metabolism within the Department of Pediatrics at The Children’s Hospital of Philadelphia. Dr. Falk is also the Organizer and Co-director of the Ophthalmology-Genetics Clinic at the same institution. She holds multiple roles including Director and Attending Physician of the Twice-Monthly Mitochondrial-Genetics Diagnostic Clinic and Attending Physician of the Monthly General Genetics Clinic. Her research expertise focuses on mitochondrial disease, the genetic basis of Mendelian disease, and developing C. elegans models of mitochondrial disease and therapy. Her clinical expertise includes mitochondrial disease, ophthalmologic genetic disease, and clinical genetics. Dr. Falk is a founding member of the Center for Mitochondrial and Epigenomic Medicine (CMEM) and the Executive Director of the Mitochondrial Medicine Center and Frontier Program at the Children’s Hospital of Philadelphia. Her work involves understanding mitochondrial disorders, their genetic underpinnings, and exploring therapeutic strategies.

Research topics

• Biology
• Medicine
• Internal medicine
• Genetics
• Bioinformatics
• Pathology
• Biochemistry
• Computational biology
• Endocrinology
• Pediatrics

Selected publications

• Cognate amino acid therapies provide preclinical benefit in 19 <i>C. elegans</i> models of ARS2 deficiency

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-05

  articleOpen accessSenior authorCorresponding

  ABSTRACT Mitochondrial aminoacyl-tRNA synthetases (mt-ARS) are essential mitochondrial translation machinery components that catalyze mitochondrial transfer RNAs (tRNAs) charging with their cognate amino acid. Although mt-ARS have a common biochemical function, patients with mt-ARS pathogenic variants commonly develop neurological disorders with varying phenotypes, severity spectrum, and age of onset. Cognate amino acid supplementation has shown reported benefits in select cases of both mt-ARS ( ARS2 ) and cytosolic ( ARS1 ) deficiencies, although the safety and potential benefits of this candidate therapy approach across the full spectrum of mt-ARS disorders remain unclear. Here, C. elegans models were systematically generated for all 19 mitochondrial mt-ARS genes by feeding RNAi knockdown for one or two generations. mt-ARS deficient animals at baseline and upon cognate amino acid treatment were studied at the level of linear growth, neuromuscular activity, lifespan, mitochondrial physiology, and fertility. Results demonstrated that cognate amino acid treatment in a dose-dependent fashion consistently improved worm linear growth and neuromuscular activity, and reduced mitochondrial unfolded protein response stress, in all 19 knockdown models. It further rescued impaired fertility of hars-1 and fars-2 knockdown strains. Collectively, these preclinical studies provide compelling evidence to warrant future cognate amino acid treatment study in rigorous clinical trials spanning all human mt-ARS deficiencies.

  PublisherOA PDFDOI

• In vitro modeling of nutritional and mitochondria-targeted therapies for osteosarcoma

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-20

  articleOpen accessSenior authorCorresponding

  Osteosarcoma is the most common pediatric bone tumor yet has limited treatment options, especially for metastatic cases with a 20% adjusted 5-year survival rate. Current therapies are non-specific, involving primary tumor resection with DNA-damaging chemotherapies like methotrexate, doxorubicin, and cisplatin. Few effective treatment options exist for metastases. Targeting metabolism involving cancers reduced mitochondrial functionality remains underexplored in osteosarcoma. We investigated the therapeutic potential in human osteosarcoma primary and metastatic cell lines of metabolic modulating drugs including metformin, cycloheximide, mitochondrial ETC inhibitors (antimycin A, metformin), dichloroacetate, and imipridones (ONC201, ONC206) on mitochondrial function and cell viability, individually and combined under various nutrient conditions across our lines. Results confirmed osteosarcoma cells are more dependent on glucose than osteoblasts but also require mitochondrial function for survival, highlighting the therapeutic potential of metabolic pathways. Osteosarcoma cell viability was reduced when any metabolic drug treatment was combined with conditions forcing reliance on mitochondrial OXPHOS capacity. Combination metabolic therapies, particularly ONC201/ONC206/metformin in 143B cells, and to a lesser extent DCA and ONC201 with either ONC206 or antimycin A, showed enhanced cytotoxicity compared to single agents, with a good therapeutic index based on minimal toxicity to normal osteoblast cells. The degree of effectiveness varied across cell lines, underscoring the importance of personalized treatment strategies. RNA-Seq transcriptome analysis revealed that effective nutrient and metabolic drug treatments triggered widespread regulatory changes in osteosarcoma cells involving increased translation/splicing with decreased mitochondrial processes such as cholesterol biosynthesis. These results demonstrate the utility of developing combined metabolic and chemotherapeutic treatments for osteosarcoma.

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• High-concentration MEHP triggers mtDNA depletion in undifferentiated HepaRG and C2C12 cultures and disrupts mitochondrial homeostasis in both HepaRG culture states

  Toxicological Sciences · 2026-04-25

  articleOpen access

  Phthalates are often called "everywhere chemicals" because they are widely used in consumer products and are detectable in the environment and humans. One of the most studied phthalates, di-2-ethylhexyl phthalate (DEHP), is metabolized to mono-(2-ethylhexyl) phthalate (MEHP), which is known to disrupt metabolic processes through peroxisome proliferator-activated receptor (PPAR) signaling. However, accumulating evidence suggests that lipophilic phthalates also affect mitochondria, key regulators of oxidative metabolism, autophagy, and apoptosis. Based on previous observations that undifferentiated cells are more sensitive to a mitotoxic agent, we hypothesized that MEHP differentially affects mitochondrial function and mitochondrial DNA (mtDNA) maintenance across hepatic cell states. To test this, we used the human HepaRG hepatoma-derived cell line, which can be cultured in undifferentiated and differentiated states, and assessed viability and mitochondrial function following prolonged 6- and 12-d high-concentration MEHP treatments. Prolonged treatments reduced viability and altered bioenergetics in both states. Short treatments (1 to 3 d) reduced viability only in differentiated cultures and were associated with mtDNA depletion in undifferentiated cultures. In both states, MEHP increased the expression of the low-molecular-weight mitochondrial genome maintenance exonuclease (MGME1) isoform, altered the levels of autophagy-related factors, and induced apoptosis. In another mitochondrial-competent myoblast model (C2C12 cells), a high concentration of MEHP was associated with mtDNA depletion, whereas lower concentrations were associated with modest reductions in cell density without detectable mtDNA loss. These results demonstrate state-dependent mitochondrial responses to MEHP and indicate that a reduced endpoint cell density is a sensitive outcome occurring independently of, and at lower concentrations than, mtDNA depletion in undifferentiated cells.

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• Targeted long-read RNA sequencing for rare disease diagnosis and variant interpretation

  Science Advances · 2026-04-15

  articleOpen access

  Diagnosing rare genetic diseases remains a major challenge despite widespread clinical testing. Long-read RNA sequencing (RNA-seq) offers a powerful approach to capturing the effects of genetic variants on the transcriptome, yet challenges with sequencing coverage, cost, tissue selection, and scalability have limited its clinical adoption. To address this, we developed STRIPE (Sequencing Targeted RNAs Identifies Pathogenic Events), a targeted long-read RNA-seq-based strategy for rare disease diagnosis and variant interpretation. STRIPE enables deep sequencing of full-length transcripts for any customized disease-specific gene panel such that a wide range of clinically informative readouts, including transcript aberrations and sequence variants, can be detected at haplotype-level resolution. Applying STRIPE to 88 individuals spanning two major rare disease groups, we accurately reidentified known pathogenic variants and revealed their transcript consequences, including many unexpected ones. For 8 of 15 splice site region variants, we observed more complex RNA processing defects beyond single exon skipping or cryptic splice site activation. Notably, we find that donor splice site variants frequently activate cryptic intronic polyadenylation sites, leading to premature transcript termination. Leveraging unique strengths of long-read RNA-seq, STRIPE also resolved variants of uncertain significance and uncovered disease-causing variants in five previously undiagnosed individuals. Overall, STRIPE is a powerful, adaptable, and scalable strategy with broad potential to improve clinical variant interpretation and advance genetic diagnosis of rare diseases.

  PublisherDOI

• A Miniaturized Enzymatic Lactate Sensor for Continuous Monitoring in Oxygen-Depleted Tissue Microenvironments

  IEEE Transactions on Biomedical Engineering · 2026-01-01

  article

  OBJECTIVE: Real-time measurement of tissue lactate levels is critical for diagnosing and monitoring metabolic disorders yet remains a challenge in dynamic physiological environments. Traditional wearable lactate sensors can provide non-invasive monitoring but are limited in their ability to capture tissue-specific information and thus diagnostic accuracy in systemic metabolic assessments. This study aims to develop an implantable microsensor for direct measurement of lactate within target tissues for continuous, real-time tracking. Recognizing that the ambient oxygen concentration in these environments may be depleted relative to oxygen concentration in, e.g., wearables, the limits of oxygen dependence of sensor operation are probed. METHODS: A miniaturized enzymatic lactate sensor (0.7×1.0×0.12 mm) was fabricated on gold electrodes with immobilized lactate oxidase, leveraging biochemical surface modifications for enhanced enzyme stability and a permselective membrane for regulation of analyte diffusion and prolonged operational lifetime in simulated biological environments. Sensor performance was evaluated electrochemically across a range of lactate concentrations. RESULTS: This sensor, tested across pathophysiological conditions, provides an expanded linear range of response (LRR) from 0.2 to 50 mM, enabling precise tracking of metabolic fluctuations with a response time of 8 s in oxygen-deficient disease microenvironments, validated by computational modelling. CONCLUSION: The sensor enables continuous monitoring of lactate levels for implantable deployment, overcoming key limitations of traditional systems in capturing local metabolic activity when tissue oxygen availability is reduced. SIGNIFICANCE: The sensor provides a platform for real-time metabolic assessment to support diagnostics, longitudinal health monitoring, and evaluation of therapeutic response in conditions such as ischemia and cancer.

  PublisherDOI

• Mitochondria transfer

  Nature Metabolism · 2025-08-27 · 13 citations

  articleOpen accessCorresponding
  PublisherOA PDFDOI

• Mitochondrial DNA Inherited Primary Retinopathies and Optic Neuropathies

  2025-07-01

  book-chapterSenior author

  Abstract The mitochondrion is a cellular organelle essential for cellular survival owing to its critical role in energy production. Mitochondrial DNA (mtDNA) pathogenic variants preferentially affect high-energy-dependent tissues such as the central nervous system, including the retina and optic nerve, and may also cause widespread multisystem organ dysfunction. Distinct retinal phenotypes with certain common features may be seen with specific mtDNA genome pathogenic variants, enabling accurate disease diagnosis, and improved clinical management approaches. This chapter discusses the most common inherited mtDNA diseases that affect retinal and optic nerve function, and details their pathophysiology, phenotypic manifestations, natural history, and emerging novel therapeutic approaches.

  PublisherDOI

• Small-molecule hypoxia therapy in mitochondrial disease

  Cell · 2025-03-01 · 1 citations

  letterOpen access1st authorCorresponding
  PublisherOA PDFDOI

• The Long‐Term Postural Orthostatic Tachycardia Syndrome Outcomes Survey‐Gynecologic Findings: A Cross‐Sectional Survey in Young Women

  Obstetrics and Gynecology International · 2025-01-01 · 2 citations

  articleOpen accessSenior author

  Objective: Postural orthostatic tachycardia syndrome (POTS) affects up to 3 million people in the United States. Although 78%–83% of POTS patients are female, gynecologic comorbidity has not been well‐studied. We created an online questionnaire to assess outcomes in female patients with POTS formerly followed at a single‐center pediatric POTS program. Design: Cross‐sectional study. Setting: Single‐center pediatric POTS program. Population or Sample: All female patients ≤ 18 years at diagnosis. Methods: We developed and distributed The Long‐Term POTS Outcomes Survey with questions about diagnosis, therapy, education, employment, social impact, quality of life (QoL), and gynecologic symptoms and management. Main Outcome Measures: Gynecologic symptoms and QoL. Results: Regular menstrual cycles were seen in 81/167 participants (49.1%). POTS symptoms worsened prior to and during menses in 118/167 subjects (72.4%); hormonal contraceptive therapy helped to control symptoms in 52/110 subjects (50%). Menorrhagia, polycystic ovary syndrome, and endometriosis were not reported in higher numbers compared to the general population. Conclusions: Menstrual flow disorders are not more prevalent in younger females with POTS. Symptoms often worsen perimenstrually, and hormone therapy can help to reduce symptom severity. Further research is needed to better define optimal hormone therapy in suppressing perimenstrual symptoms.

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• Interpreting the clinical significance of multiple large-scale mitochondrial DNA deletions (MLSMD) in skeletal muscle tissue in the diagnostic evaluation of primary mitochondrial disease

  Frontiers in Pharmacology · 2025-04-09 · 1 citations

  articleOpen access

  Background and Objectives: Improved detection sensitivity from combined Long-Range PCR (LR-PCR), Next-Generation Sequencing (NGS), and droplet digital PCR (ddPCR) to identify multiple large-scale mtDNA deletions (MLSMD) and quantify deletion heteroplasmy have introduced clinical interpretation challenges. We sought to evaluate clinical, biochemical, and histopathological phenotypes of a large clinical cohort harboring MLSMD in muscle to better understand their significance across a range of clinical phenotypes. Methods: A single-site retrospective study was performed of 212 diagnostic muscle biopsies obtained from patients referred for Primary Mitochondrial Disease (PMD) evaluation with muscle mitochondrial (mt)DNA sequencing performed at our institution, including electronic medical record (EMR) review of symptoms, biochemical results, and Mitochondrial Myopathy Composite Assessment Tool (MM-COAST) scores. Results: MLSMD were identified in 50 of 212 (24%) diagnostic tissue biopsies, and were universally present. in subjects ≥50 years (n = 18/18). In 45 of 50 (90%) subjects with MLSMD, no definitive genetic etiology was identified, despite clinical whole exome sequencing (WES) and/or whole genome sequencing (WGS). MLSMD heteroplasmy levels quantified by ddPCR ranged from 0% to 33%, exceeding 10% heteroplasmy in 5/45 (11%). Subjects with MLSMD (n = 45) were more likely to demonstrate mitochondrial abnormalities on histopathology, upregulation (≥150% of control mean) of one or more electron transport chain (ETC) complex enzyme activities, and reduced citrate synthase indicative of mitochondrial depletion (<60% of control mean) relative to subjects without MLSMD (n = 155). As clinical phenotypes varied across the MLSMD cohort, Bernier diagnostic criteria major/minor symptoms were used to discriminate 13 of 45 subjects with "suspected" PMD having unrevealing WES/WGS results and 32 of 45 subjects scored as "less likely" to have PMD. Relative to the "less likely" cohort, a significantly higher frequency of biochemical and muscle histopathological abnormalities (ragged red and COX negative fibers) were observed in the "suspected" cohort, further supporting a higher index of suspicion for PMD, p < 0.05. Discussion: MLSMD in skeletal muscle tissue were a common molecular finding (24%) in our cohort and consistently present in subjects ≥50 years. Among those with genetically undiagnosed MLSMD (n = 45), the "suspected" PMD subset (n = 13/45) represent a promising cohort for novel gene discoveries.

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Recent grants

• Pharmacologic Treatment of Mitochondrial Complex I Dysfunction in C. Elegans

  NIH · $2.4M · 2010–2021

• Mitochondrial respiratory chain disease mechanistic and therapeutic modeling

  NIH · $3.7M · 2020–2030

• NIH Grant K08DK073545

  NIH · $666k · 2011

• NIH Grant R03DK082521

  NIH · $157k · 2011

• NIH Grant R01HD065858

  NIH · $1.6M · 2016

Frequent coauthors

• Xiaowu Gai

  University of Southern California

  117 shared

• Elizabeth M. McCormick

  University of Pennsylvania

  116 shared

• Zarazuela Zolkipli‐Cunningham

  Children's Hospital of Philadelphia

  100 shared

• Rebecca Ganetzky

  Children's Hospital of Philadelphia

  94 shared

• Amy Goldstein

  University of Pennsylvania

  93 shared

• Shana E. McCormack

  Children's Hospital of Philadelphia

  72 shared

• Bruce H. Cohen

  Boston Medical Center

  66 shared

• Richard Haas

  University of California, San Diego

  64 shared

Labs

• Falk LabPI