Latest Paper – Mito’ KNa1.2 Channel

Our paper on a mitochondrial KNa1.2 channel is now out as a pre-print at BioRxiv. It describes about 4 years of work by Owen Smith, a (hopefully soon to be graduated) student in the lab.

This new report builds off our paper last year showing that KNa1.2** is required for cardioprotection by volatile anesthetic preconditioning (APC). In that paper, we kind-of showed that there’s a mitochondrial KNa1.2 channel, but the gold standard is patch-clamp of isolated mito’ inner membranes (mitoplasts) and, to put it mildly, this is not a simple technique! With the help of Liz Jonas at Yale and Casey Kinally at NYU (now retired), Owen finally cracked it and we now have solid evidence the channel exists in mitochondria.

The next question was “OK, if this channel exists, it didn’t evolve over millions of years waiting for volatile anesthetics to be invented in the 20th century, so what’s its endogenous physiologic role?”  What we found is that the hearts of channel knockouts have a rather odd metabolic phenotype – they can’t exhibit maximal respiratory or work capacity, BUT this is only true when they’re burning fat as a fuel. They’re perfectly OK on glucose, and they’re fine at baseline, they just can’t go full-speed when burning fat.

This finding has some interesting implications…. First, it implies a mechanistic link between a mitochondrial potassium channel and the regulation of cardiac metabolism. To the best of our knowledge this is the first such reported link.  Second, we found that activating mito’ KNa1.2 uncouples mitochondria, and it was reported in 2014 that Niclosamide, a KNa activator, is beneficial in a high fat diet model of diabetes. Ergo, this mito’ channel could be an important (and so far overlooked) drug target for regulating metabolism, with potential importance for obesity, diabetes, metabolic syndrome etc.

Anyway, while the paper is being reviewed at a “regular” journal (fingers crossed), the pre-print hopefully gets the story out there for critique by the field at large. If you have something to say  – have at it in the BioRxiv comments, or Tweet/E-mail me. Our previous pre-prints have benefitted enormously from incorporation of comments on BioRxiv at the journal revision stage.

**For those confused by the naming, KNa1.2 is the new name for “Slo2.1”, which is also known as “Slick”, and is encoded by the Kcnt2 gene. We used to call it by the Slo nomenclature, since Slo2.1 is part of a larger family of channels related to the Drosophila slow-poke allele, which is Slo1. Slo1 is a KCa channel, whereas Slo2.1 and its sibling Slo2.2 (aka KNa1.1, Slack) are KNa channels.