Abstract
Isoniazid (INH), a widely used first-line antitubercular drug, has been noted to be associated with hepatotoxicity. In spite of extensive researches over many decades, the mechanism of INH-induced hepatotoxicity still remains poorly understood. Recently, mitochondrial toxicity has been emerging as a new paradigm for INH-induced hepatotoxicity. In this study, we showed that INH impaired mitochondrial biogenesis and dynamics in human hepatocarcinoma HepG2 cells. INH reduced mitochondrial membrane potential (MMP) and induced mitochondria swelling. INH also inhibited the protein expressions of three major mitochondrial biogenesis regulators, SIRT1, PGC1α and NRF1, along with increased acetylation of PGC1α. Meanwhile, INH decreased the number of mitochondria, accompanied by decreased expression of mitochondrial protein COX IV. INH caused mitochondrial fragmentation involving decreased levels of the fusion protein MFN2 as well as the fission protein DRP1. INH-reduced DRP1 expression was associated with the increase of apoptosis, suggesting the existence of pro-survival fission and its involvement in mitochondrial quality control. INH activated p38 MAPK, whereas inhibition of p38 MAPK aggravated INH-induced decreases of SIRT1, PGC1α, NRF1, COX IV and DRP1 expressions. P38 MAPK inhibition also further up-regulated the acetylation of PGC1α and exacerbated INH-induced MMP loss, mitochondrial swelling and apoptosis. Taken together, INH-activated p38 MAPK induced mitochondrial biogenesis to alleviate apoptosis through partly recovering SIRT1-PGC1α pathway activation. In the meantime, p38 MAPK activation by INH promoted protective mitochondrial fission to alleviate apoptosis by partial recovery of DRP1 expression.
Highlights
Isoniazid is a widely used first-line agent for the treatment of tuberculosis
Compared with INH treatment alone, INH together with Mdivi-1 significantly enhanced apoptosis induction, evidenced by elevated cleavage of apoptotic protein of procaspase 3 (Figure 5D). These results suggested that mitochondrial fission caused by dynamin-related protein 1 (DRP1) might contribute to the elimination of impaired mitochondria, and that p38 MAPK worked for the protection from apoptosis by up-regulation of DRP1
When mitochondria become unstable due to various stresses, mitochondrial biogenesis and dynamics contribute to mitochondrial homeostasis
Summary
Isoniazid is a widely used first-line agent for the treatment of tuberculosis. Despite the therapeutic benefits of this drug, it has been reported that INH mildly increased plasma alanine aminotransferase (ALT) levels up to approximately 20% in patients and that hepatotoxicity occurred in 1 of every 1,000 individuals treated with INH (Maddrey and Boitnott, 1973; Black et al, 1975; Nolan et al, 1999; Lee, 2003; Centers for Disease Control and Prevention [CDC], 2010). INH-induced hepatotoxicity has contributed to the emergence of multidrugresistant strains of Mycobacterium tuberculosis, thereby limiting its application during the past decades (Tostmann et al, 2008). Multiple pathways are involved in INH-induced hepatotoxicity, such as oxidative stress, immune response and disruption of endogenous metabolism (Boelsterli and Lee, 2014). The classical paradigms for INH-induced hepatotoxicity have been changed over the past years (Zhai et al, 2008; Yue and Peng, 2009; Cheng et al, 2013). Mitochondrial stress has been emerging as a new paradigm for INH-induced hepatotoxicity (Lee et al, 2013; Boelsterli and Lee, 2014)
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