Letter to the editor: Compromised hepatic mitochondrial fatty acid oxidation and reduced markers of mitochondrial turnover in human NAFLD

To the editor, We read the recent study by Moore et al.[1] reporting that compromised hepatic fatty acid oxidation (FAO) and mitochondrial turnover are closely related to NAFLD severity in obese patients. The article greatly increases our understanding of the role of mitochondria in the pathogenesis of NAFLD, but we still had some concerns about the results that require attention. First, mitochondrial homeostasis, a prerequisite for mitochondrial functions, is majorly orchestrated by mitochondrial biogenesis and mitophagy. The perturbation between mitochondrial biogenesis and mitophagy causes the dysfunction of the mitochondria pool, which results in less ATP production and more reactive oxygen species (ROS) generation.[2] Hepatic mitochondrial biogenesis, mitophagy, and dynamics of patients with B‐NASH and D‐NASH were impaired in the current study, which further contribute to round, swollen, hypodense mitochondria with loss of cristae. The declined ATP production and accumulated ROS generation are a sure result. However, the protein content of hepatic OXPHOS complexes did not differ across groups. At the same time, the whole‐liver antioxidant defense system markers of protein content are not declined. Altogether, it is hard to explain that the mitochondrial ATP and ROS generation were significantly changed. It is well known that mitochondrial superoxide generated from the electron leak from Complexes I and III of electron transport chain during ATP production, and dysfunctional complex I and III trigger more superoxide generation.[3] We think that it is necessary to provide evidence of complex I and III activity not only for the ROS accumulation but also for the less energetic metabolism. Second, peroxisome proliferator‐activated receptor‐gamma coactivator (PGC‐1α), a co‐activator of peroxisome proliferator‐activated receptor gamma (PPARγ), is considered the master transcriptional regulator of mitochondrial biogenesis, but it is not enough to indicate the mitochondrial biogenesis by itself. PGC‐1a interacts with different transcription factors participating in multiple cellular activities including mitochondrial biogenesis, adaptive thermogenesis, angiogenesis, regulation of tricarboxylic acid cycle, gluconeogenesis, FAO, and oxidative phosphorylation.[4] Therefore, the dramatic reduction of mitochondrial biogenesis needs more evidence to confirm. Mitochondrial transcription factor A and mitochondrial DNA copy represent the direct mitochondrial biogenesis and need to be further determined. It should be noticed that deficient mitophagy might lead to damaged mitochondria accumulation, contributing to mDNA copy increase. Finally, mitophagy, a specific autophagic elimination of mitochondria, shares the most of molecular mechanic machinery with autophagy; thus, the interpretation of mitophagy needs more careful review. However, the study only detected the protein content of BCL2/adenovirus E1B19 kDa‐interacting protein 3 (BINP3), Phosphatase and tensin homolog (PTEN)‐induced kinase 1 (PINK1), and Parkinson's disease protein (PARKIN) of hepatic mitochondria. In actuality, the accumulated P62 and LC3 on mitochondria are more important to mitophagic flux.[5] We recommend that the authors further detect the P62 and LC3 of hepatic mitochondria. Another question to be answered is why a low level of ethanol is a mitochondrial biogenesis activator. In conclusion, we agree with the investigators’ conclusion that compromised hepatic FAO and dysfunctional mitochondria are closely related to NAFLD severity in obese patients. However, further studies are required to determine the mitochondrial biogenesis, the mitophagy, and the Complexes’ activity alteration in obese patients with NAFLD. CONFLICT OF INTEREST Nothing to report.