Introduction: Previous studies have shown that the proper functioning of both mitochondria and the glymphatic system transporting metabolites are essential for brain health. The aim of this systematic review was to identify the current evidence-based data regarding the relationship between mitochondria and the glymphatic system.

Methods: This systematic review was conducted following PRISMA guidelines. The databases of PubMed, Scopus, Medline, and Web of Science were searched on June 11, 2024, for eligible studies published until June 1, 2024.

Results: Of 103 studies, six were included: two original studies and four review articles. All the included studies consistently indicated that the mitochondria and the glymphatic system are likely interconnected, with evidence suggesting several potential links between them. According to original studies, mitochondrial abnormalities in idiopathic normal pressure hydrocephalus (iNPH) and idiopathic intracranial hypertension (IIH) may disrupt glymphatic system function. The included reviews highlighted REM sleep deprivation, melatonin, and inflammation as potential factors linking mitochondria and the glymphatic system.

Discussion: The relationship between mitochondria and the glymphatic system is complex. Further research is needed to clarify the precise mechanisms of interaction as the current literature is largely speculative. Existing evidence suggests that mitochondrial abnormalities are present in iNPH and IIH, conditions related to impaired CSF flow and impaired glymphatic function. In addition, sleep and melatonin potentially link mitochondrial activity and the glymphatic system function and thus offer potential avenues to ameliorate disorders associated with glymphatic dysfunction by enhancing mitochondrial activity.