Introduction Pathogenic variants in the gene encoding the catalytic subunit of DNA polymerase gamma (POLG), comprise an important single-gene cause of inherited mitochondrial disorders. Clinical manifestations are now recognised as an array of overlapping clinical features rather than discrete syndromes as originally conceptualised. Animal and cellular models have been used to address numerous scientific questions, from basic science to the development and assessment of novel therapies. Here, we sought to perform a systematic review of the existing models used in mitochondrial research and their effectiveness in recapitulating POLG-related disease. Methods Four databases were searched from inception to May 31, 2022: MEDLINE, Scopus, Web of Science, and Cochrane Review. Original articles available in English, reporting the use of a model system designed to recapitulate POLG-related disease, or related pathogenicity, were eligible for inclusion. Risk of bias and the methodological quality of articles were assessed by an adapted version of the Cochrane Risk of Bias Tool, with the quality of evidence synthesized across each model. Results A total of 55 articles, including seven model organisms (Human, yeast [Saccharomyces cerevisiae and Schizosaccharomyces pombe], Drosophila, Mouse, Nematoda, and Zebrafish) with 258 distinct variants were included. Of these, 66% (N=38) of articles recapitulated mitochondrial DNA (mtDNA) depletion and 42% (N=23) recapitulated POLG-related disease. Thirty-three percent of articles (N=18/55) utilised tissue-specific models of POLG-related dysfunction, while 13% (N=7) investigated the effect of potential therapeutics in POLG-related mitochondrial disorders. Discussion The available evidence supporting the ability of models for POLG-related disease to recapitulate molecular mechanisms and phenotype is limited, inconsistent and of poor methodologic quality. Further success in examining and translating novel therapies into effective treatments will be enhanced by the availability of more robust models that better recapitulate the entire spectrum of POLG-related disease. PROSPERO registration: CRD42021234883
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