# Enhancing Mitochondrial Function Through Pharmacological Modification: A Novel Approach to Mitochondrial Transplantation in a Sepsis Model

## TL;DR

This study explores using drugs to improve mitochondria before transplanting them into sepsis cells, which may help reduce inflammation and improve outcomes.

## Contribution

The novel approach of enhancing mitochondrial function with drugs like formoterol before transplantation in sepsis is introduced.

## Key findings

- Formoterol significantly increased mitochondrial biogenesis and oxygen consumption rates.
- Formoterol-enhanced mitochondrial transplantation reduced TNF-α levels in LPS-induced THP-1 cells.
- Mitochondrial-associated genes like PGC-1α and mt-Cytb were upregulated with formoterol treatment.

## Abstract

Background/Objectives: Sepsis continues to be a significant global health issue, with current treatments primarily focused on antibiotics, fluid resuscitation, vasopressors, or steroids. Recent studies have started to explore mitochondrial transplantation as a potential treatment for sepsis. This study aims to evaluate the effects of enhanced mitochondrial transplantation on sepsis. Methods: We examined various mitochondrial-targeting drugs (formoterol, metformin, CoQ10, pioglitazone, fenofibrate, and elamipretide) to improve mitochondrial function prior to transplantation. Mitochondrial function was assessed by measuring the oxygen consumption rate (OCR) and analyzing the expression of genes related to mitochondrial biogenesis. Additionally, the effects of enhanced mitochondrial transplantation on inflammation were investigated using an in vitro sepsis model with THP-1 cells. Results: Formoterol significantly increased mitochondrial biogenesis, as evidenced by enhanced oxygen consumption rates and the upregulation of mitochondrial-associated genes, including those related to biogenesis (PGC-1α: 1.56-fold, p < 0.01) and electron transport (mt-Nd6: 1.13-fold, p = 0.16; mt-Cytb: 1.57-fold, p < 0.001; and mt-Co2: 1.44-fold, p < 0.05). Furthermore, formoterol-enhanced mitochondrial transplantation demonstrated a substantial reduction in TNF-α levels in LPS-induced hyperinflammatory THP-1 cells (untreated: 915.91 ± 12.03 vs. formoterol-treated: 529.29 ± 78.23 pg/mL, p < 0.05), suggesting its potential to modulate immune responses. Conclusions: Mitochondrial transplantation using drug-enhancing mitochondrial function might be a promising strategy in sepsis.