Mitochondrial transplantation and platelet rich plasma for the treatment of non-alcoholic fatty liver disease

Table 1 Mitochondrial dysfunction and oxidative stress in liver diseases

Liver disease	Main pathological alterations	Role of oxidative stress	Role of mitochondrial dysfunction	Ref.
NAFLD	Hepatic lipid accumulation, mild inflammation, metabolic dysregulation, lipid accumulation, altered autophagy and mitochondrial quality control	Increased ROS production promotes lipid peroxidation and mild inflammatory response, oxidative stress contributes to progression toward NASH	Early mitochondrial damage affects lipid metabolism and redox balance, drives lipid dysregulation, impairs energy homeostasis, and alters mitochondrial turnover	Zheng et al[38], Dabravolski et al[39], and Trinchese et al[40]
NASH	Steatosis, inflammation, hepatocyte injury and fibrosis	ROS and RNS overproduction activate NF-κB and upregulate TNF-α, IL-1β, IL-6, IL-8	mtDNA release activates TLR9-mediated inflammation; mitochondrial damage enhances lipotoxicity and fibrosis	Simões et al[11], Rodrigues et al[28], and Carter-Kent et al[41]
HCC	Cell proliferation, somatic mutations, altered mitochondrial dynamics (fusion/fission, mitophagy)	ROS promote DNA damage and tumor progression, oncogenic signaling, and resistance to apoptosis	Mitochondrial dysfunction enhances Warburg effect	Chen et al[42] and Su et al[43]

NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; HCC: Hepatocellular carcinoma; ROS: Reactive oxygen species; RNS: Reactive nitrogen species; IL: Interleukin; TNF-α: Tumor necrosis factor α; NF-kB: Nuclear factor-kappa B.

Table 2 Regenerative mechanisms and applications of platelet rich plasma in preclinical and clinical studies

Model/disease	Outcomes and mechanism	Ref.
Porcine and human cartilage cells/osteoarthritis	Stimulated chondrocyte proliferation, cartilage matrix production, suppressed inflammation via NF-κB inhibition	Monteiro et al[66]
Equine tenocytes, tendinopathies	Protected against hydrogen peroxide damage, reduced protein and lipid peroxidation, prevented cell death, increased nuclear Nrf2 levels, induced antioxidant enzyme expression	Tognoloni et al[71]
Human anterior cruciate ligamentocytes, ligament injury	Increased DNA content and metabolic activity (cell proliferation), no significant extracellular matrix production	Krismer et al[72]
Rabbits, osteoarthritis	Enhanced cartilage repair, increased glycosaminoglycan production	Monteiro et al[66]
Horses, osteoarthritis	Alleviated lameness	Monteiro et al[66]
Mice, cirrhosis	PRPEV reduced liver fibrosis, promoted hepatocyte proliferation, increased anti-inflammatory M2 macrophages	Maeda et al[73]
Rats, chronic liver disease	Improved liver enzymes, lipid profile, oxidative stress markers	Mansour et al[74]
Rats, bile duct ligation-induced cirrhosis	ADMSCs + PRP reduced inflammation, hepatocyte damage, collagen deposition	Shivaramu et al[75]
Humans (30 patients), knee osteoarthritis	Reduced pain by 33.4%	Monteiro et al[66] and Kwon et al[70]

Nrf2: Nuclear factor erythroid 2-related factor 2; PRPEV: Platelet-rich plasma-derived extracellular vesicles; ADMSC: Adipose-derived mesenchymal stem cell; PRP: Platelet rich plasma.