Research Highlights

collected from people representing published the first report of Journal Club all major global populations. mtDNA mutations causing a The most important discovery of disease — Leber’s hereditary optic mtDNA in the crossroads of their work was that the highest neuropathy. As disease-causing​ evolution and disease degree of mtDNA variation was mutations are amenable to natural found among Africans, attesting to selection, how could one consider Mitochondrial DNA (mtDNA) their anti­quity. The other finding the mtDNA to be merely a neutral sequences are currently studied was that although mtDNA from marker? It was this contradiction mainly by three disciplines: across the globe contained African that drew me into studying molecular evolution (including types, Africans had many unique mitochondrial biology and to anthropology), functional mtDNA types. discovering that even common genomics and analyses of genetic These two findings, in addition population variants of mtDNA are disorders. Strangely, these discip­ to other data, prompted Cann et al. both subjected to natural selection lines can use the relatively short mtDNA (1987) to propose that the origin and alter the tendency to develop sequence of mtDNA in opposing has been of all current human populations genetic disorders. manners, by attributing to it either considered (at least the maternal lineage) is Dan Mishmar Department of Life Sciences, lack of function, as is the case an excellent likely African. Many criticized in (some) molecular evolution this study, especially because Ben-Gurion​ University of the Negev, marker for Be’er-​Sheva, Israel. studies, or conversely, functional their African samples originated e-mail:​ [email protected] mainly from Afro-Americans​ relevance in the aetiology of tracing ancient The author declares no competing interests genetic disorders. migrations rather than from indigenous In the field of molecular evolu- African populations. Nevertheless, Original articles Cann, R. L. et al. because of its Mitochondrial DNA and human evolution. tion, mtDNA has been considered subsequent studies, which used Nature 325, 31–36 (1987) | Wallace, D. C. et al. an excellent marker for tracing uniparental more advanced techniques and Mitochondrial DNA mutation associated ancient migrations because of its better-sampled​ populations, with Leber’s hereditary optic neuropathy. (maternal) Science 242, 1427–1430 (1988) | Mishmar, D. et al. uniparental (maternal) inheritance inheritance supported this pioneering Natural selection shaped regional mtDNA and lack of recombination.­ These and game-​changing work of variation in humans. Proc. Natl Acad. Sci. USA and lack of 100, 171–176 (2003) | Marom, S. et al. mtDNA characteristics prompted Cann et al. MtDNA meta-analysis reveals both phenotype Rebecca Cann, Mark Stoneking recombination In the year following the specificity and allele heterogeneity: a model and Allan Wilson to analyse the publication of the above article, for differential association. Sci. Rep. 7, 43449 (2017) mtDNA in 147 human samples Douglas C. Wallace and colleagues

MECHANISMS OF DISEASE AMPK against NASH Non-alcoholic steatohepatitis (NASH) is activation were elevated in LAKO mice the most severe form of non-alcoholic on NASH-inducing diets. Depletion or fatty liver disease (NAFLD), which is inhibition of caspase 6 counteracted tightly linked to overnutrition and NASH-associated liver pathology in obesity. Hepatic cell death, including these mice. Caspase 6 activity was also apoptosis, is an important driver of NASH increased in other mice models of NASH pathology. Saltiel and colleagues now and in liver samples from patients with

show that NASH-associated hepatocyte NASH, indicating a key role of caspase 6 Limited Nature /Springer S.Bradbrook Credit: apoptosis is inhibited by AMPK — a in hepatocyte apoptosis in NASH. Application of an agonist of AMPK to major sensor of cellular energy status. Mechanistically, pro-caspase 6 acti- mice with diet-induced NASH was asso- AMPK downregulation was previously vation was shown to rely on caspase 3 ciated with pro-caspase 6 phosphoryl­ associated with NAFLD. In line with and caspase 7, which are major exe­ ation and with reduced caspase 6 activity. this, mice on NASH-inducing diets had cutioners of apoptosis. Following acti- This approach also significantly reduced reduced AMPK activity. Furthermore, vation, caspase 6 promoted the release the number of apoptotic cells and allevi­ generation of liver-specific AMPK of cytochrome c from mitochondria, ated liver damage. Thus, targeting the knock-out (LAKO) mice demonstrated thereby supporting activation of the AMPK is an AMPK–caspase 6 axis could be explored that loss of AMPK exaggerates diet- executioner caspases and apoptosis as a new therapy for NASH. induced NASH pathology, including in a feed-forward mechanism. inhibitor of increased liver damage, fibrosis and Pro-caspase 6 was directly phosphoryl- caspase Paulina Strzyz cell death — specifically apoptosis. ated by AMPK, and activation of AMPK 6-driven Original article Zhao, P. et al. An AMPK– Apoptosis is driven by the caspase reduced pro-caspase 6 cleavage in a cell caspase-6 axis controls liver damage in nonalcoholic hepatic cell steatohepatitis. Science 367, 652–660 (2020) cascade, which involves a series of culture model of hepatotoxicity. Together Related article Herzig, S. & Shaw, R. J. protein cleavage and activation steps. with the data from LAKO mice, this indi- death AMPK: guardian of metabolism and mitochondrial Cleavage of pro-caspase 6 to its cated that AMPK is an inhibitor of caspase homeostasis. Nat. Rev. Mol. Cell Biol. 19, 121–135 (2018) mature form and subsequent caspase 6 6-driven hepatic cell death in NASH.

NATuRe RevIewS | MoleCular Cell Biology volume 21 | APRIL 2020 | 181