Mitochondrial transplantation for delirium superimposed on dementia: from pathogenic mechanisms to clinical translation challenges.

Delirium Superimposed on Dementia (DSD) is a common neuropsychiatric disorder in hospitalized elderly populations with poor prognosis, which can accelerate cognitive decline and increase mortality. Despite its clinical significance, there is a lack of effective therapeutic methods in clinical practice. Mitochondrial dysfunction, characterized by impaired energy metabolism, excessive reactive oxygen species (ROS) production and neuroinflammation activation, has been suggested as a potentially critical pathogenic link in DSD. As an emerging organelle-based therapy, mitochondrial transplantation (MTT) restores cellular energy homeostasis and mitigates oxidative stress by delivering functional mitochondria into damaged cells, thus holding promising potential as a future strategy for DSD treatment. This review systematically summarizes the hypothesized pathological role of mitochondrial dysfunction in DSD and the technical system of MTT, including mitochondrial isolation, purification, preservation and delivery strategies. We further elaborate on the plausible neuroprotective mechanisms of MTT and its preclinical evidence in neurodegenerative disease models relevant to, but distinct from, DSD. Additionally, we comprehensively analyze the technical, immunological and clinical challenges of MTT in DSD treatment, and propose targeted solutions and future research directions. This review constructs a theoretical framework for the hypothetical translation of MTT from basic research to clinical application in DSD, and provides novel insights for the development of future etiological therapies for this devastating disorder.