Exploration of Digestive Diseases

Table 1. Changes in mitochondrial lipid composition in different disease models of MASLD, ARLD, and HCC

Lipids		Mitochondrial changes	Disease outcomes	Disease model
Fatty acids		↑ mitochondrial fatty acid β-oxidation at early stages	ARLD [66] MASLD [67]	Mice
		↓ mitochondrial fatty acid β-oxidation at advanced stages	ARLD [68–70] MASH [67, 68, 71]	Mice
		↓ nicotinamide adenine dinucleotide (NAD⁺/NADH) levels in mitochondria	ARLD [69] MASLD [68]
		↑ carnitine palmitoyltransferase-1 in mitochondrial membrane	MASLD [67]	Mice
		↑ lipid peroxidation in mitochondria	ARLD [72] MASLD [71] MASH [71]	Rat HepG2
		↓ ETC coupling (CI, CIV)	MASLD [71] MASH [67, 71]	Mice
		↓ mitophagy mediated by NLRP3 activation and AMPK inhibition	MASLD [73, 74]	Mice Cells
		↑ mitochondrial attachment to lipid droplets because of diacylglycerol-O-acyltransferase-2 increased activity	MASLD [67]
		↑ lipid peroxidation in mitochondria	ARLD [72] MASLD [71] MASH [71]	Rat HepG2
		↓ mesh due to altered mitochondrial membrane composition	ARLD [75, 76] MASLD [68]	Rat
Glyceride	Diacylglycerides	↑ pyroptosis via NLRP3 activation	MASH [77]	Mice Human
	Triglycerides	↑ mitochondrial oxidative flux	MASLD [68]
		↓ membrane fluidity if the cholesterol/triglycerides ratio is altered	ARLD [76]	Rat
		↑ tumor anabolism	HCC [78]
Phospholipid	Cardiolipin	↑ NLRP3 and apoptosis by CL peroxidation and redistribution from IMM to OMM	ARLD [69, 75, 76] MASLD [68]	Rat
		↓ ETC complex activity (CI, CIII, CIV, and ADP/ATP carrier)	ARLD [69] MASLD [67, 71, 79]	Rat
		↑ mPTP opening and cytochrome c release by Bcl-2 family proteins interaction (Bax)	ARLD [80] MASLD [67, 71] MASH [80]	Rat
	Phosphatidylcholine	↓ mitochondrial ROS production by CYP2E1 inhibition	ARLD [72]
	Phosphatidylcholine	↑apoptosis due to changes in mitochondrial phosphatidylcholine redox state and through JNK activation	ARLD [76] MASLD [68, 79] MASH [68, 77]	Mice Rat Human
	Phosphatidylethanolamine	↓ membrane fluidity	ARLD [76]
Sphingolipid	Ceramide	↑mitochondrial ROS generation and apoptosis by TNFα/Fas signaling	ARLD [70, 75, 81] MASLD [68, 73] MASH [81]	PMH
		↓ ETC (CIII)	ARLD [70] MASH [67]	Mice
		↓ mitochondrial fatty acid β-oxidation	MASLD [68] MASH [67]	Mice
		↓ mitophagy through NLRP3 activation	MASLD [73]
		↓ mitochondrial membrane permeabilization	HCC [82]	Cell line
		↑ mitochondrial depolarization	MASLD [82]
	Ganglioside	↑ ETC (CIII)	MASH [67]
Sterol	Cholesterol	↑ mitochondrial ROS production	ARLD [75, 83] MASH [83]	Cells Human
		↓ ETC (CI)	MASLD [84] ARLD [69] HCC [83]
		↑survival by a defective assembly of the apoptosome	HCC [80, 83]	Rat
		↓ mitochondrial membrane permeabilization	ARLD [75, 76, 83] MASLD [84] MASH [67, 83, 85] HCC [80, 83]	HepG2 Mice Rats Monkeys Human
		↓ mitochondrial protein transport (SLC25A11) by TNFα and Fas-induced apoptosis	ARLD [69, 75, 80, 83, 86] MASH [80, 83, 85, 87]	PMH Mice Human
		↑ mitochondrial fusion (megamitochondria)	ARLD [69]	Mice
		↑ mPTP by JNK-dependent proinflammatory pathway	ARLD [75] MASH [68]	PMH
		↑ alternative (acidic) bile synthesis pathway	MASLD [84] MASH [88, 89] HCC [88]	PRH Mice
Lipid droplets		↓ motility and fusion rates of peridroplets mitochondria	MASLD [67]
		↑ megamitochondria through fusion-fission rates alteration	ARLD [66]	Mice
		↑ function of cytosolic mitochondria	MASLD [90] HCC [90]

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MASLD: metabolic dysfunction-associated steatotic liver disease; ARLD: alcohol-related liver disease; HCC: hepatocellular carcinoma; MASH: metabolic-associated steatohepatitis; ETC: electron transport chain; NLRP3: NLR family pyrin domain containing 3; IMM: inner mitochondrial membrane; OMM: outer mitochondrial membrane; mPTP: mitochondrial permeability transition pore; ROS: reactive oxygen species; JNK: c-Jun N-terminal kinase; TNFα: tumor necrosis factor-alpha

Declarations

Acknowledgments

Cartoons in Figures were created with BioRender.com. Carmen Garcia-Ruiz and José C. Fernández-Checa acknowledge the support of the Spanish National Research Council’s Cancer Hub.

Author contributions

LF and LCdlR: Conceptualization, Writing—original draft, Writing—review & editing. JCFC and CGR: Conceptualization, Writing—original draft, Writing—review & editing, Funding acquisition, Supervision. All authors have read and agreed to the published version of the manuscript.

Conflicts of interest

Prof. José C. Fernández-Checa is the Editor-in-Chief of Exploration of Digestive Diseases, and Prof. Carmen Garcia-Ruiz is a member of the Editorial Board and a Guest Editor of Exploration of Digestive Diseases. However, neither was involved in the decision-making or review process for this manuscript.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

We are grateful for the support from grants [PID2020-115055RB-I00], [PID2022-1429560B-I00] and [2023AEP068] from Plan Nacional de I+D funded by the Agencia Estatal de Investigación (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER) and from the CIBEREHD; as well as support from AGAUR of the Generalitat de Catalunya [SGR-2021-00491], European Cooperation in Science & Technology (COST) [ACTION CA17112], Prospective European Drug-Induced Liver Injury Network, the 2018-102799-T “Enfermedades Metabólicas y Cancer” from the Red Nacional of the Spanish Health Ministry and the COVID grant from the Spanish Association for the Study of the Liver (AEEH). In addition, this project has received funding from the European Horizon’s research and innovation program HORIZON-HLTH-2022-STAYHLTH-02 under agreement No [101095679]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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