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Create in EPUB, convert to MOBI as necessary.
For pictures, my general rule of thumb is to use PNG format for line-art, and JPEG for photographs or similar (e.g. old etchings). There's some middle ground in the quality vs. space vs. intended audience tradeoff where it's equally valid to use one or the other. In particular, JPEG encoding of the high-contrast edges which are inevitable in line-art tends to cause a "halo" or "blooming" effect, which is more noticeable at lower quality levels. But this halo is often so faint that you won't notice it on an e-ink screen (although it's more visible on the LCD screen of e.g. a Kindle Fire). So, "it depends".
You should also know that until yesterday's release, Calibre would convert ALL pictures into JPEGs when converting EPUB to MOBI, in order to avoid compatibility problems with older e-readers that sometimes had problems with PNGs and GIFs. There's now an option to disable that behavior...
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