Segmental COX-Negative Fibers

Clinical History

This 40-year-old female who presented with generalized muscle weakness, progressive ptosis and cognitive impairment.

Question

What of the following is the most likely diagnosis based on figures #1 and #2?

A. Polymyositis

B. IBM

C. Sarcoidosis

D. Mitochondrial myopathy

Answer – Mitochondrial Myopathy

The correct answer is D. Mitochondrial myopathy.

Figure 1: Modified Gomori Trichrome frozen section and EM

Modified Gomori Trichrome showed scattered muscle fibers with increased mitochondrial type staining, including occasional ragged-red muscle fibers (arrow).

Electron microscopy demonstrated frequent muscle fibers containing mitochondria with abnormal architecture (enlarged with spiral arrangement of crista) and/or containing paracrystalline inclusions.

Figure 2: Frozen section combined COX-SDH

Combined COX-SDH enzyme histochemical stain showed frequent “COX-negative” muscle fibers (fibers which show absence of brown COX staining but intact blue SDH staining).

Note the striking segmental nature of the COX-negative staining in this case.

Mitochondrial Myopathy

• The cells of your body coordinate two genomes: the nuclear genome (nDNA) which encodes SDH and the mitochondrial genome (mtDNA) which encodes COX.
• Recent research has shown that there are different populations of mitochondria in muscle (subsarcolemmal and intermyofibrillar) and that these form and interconnecting network. The segmental pattern of COX-negative staining is thought to possibly reflect a biologic safety mechanism of the mitochondrial “power grid.” Please see reference for additional information.

Reference(s)/Additional Reading:

• Willingham TB, Ajayi PT, Glancy B. Subcellular Specialization of Mitochondrial Form and Function in Skeletal Muscle Cells. Front Cell Dev Biol. 2021 Oct 15;9:757305. doi: 10.3389/fcell.2021.757305. PMID: 34722542; PMCID: PMC8554132.
• Picard M, White K, Turnbull DM. Mitochondrial morphology, topology, and membrane interactions in skeletal muscle: a quantitative three-dimensional electron microscopy study. J Appl Physiol (1985). 2013 Jan 15;114(2):161-71. doi: 10.1152/japplphysiol.01096.2012. Epub 2012 Oct 25. PMID: 23104694; PMCID: PMC3544498.
• Glancy B, Hartnell LM, Combs CA, Femnou A, Sun J, Murphy E, Subramaniam S, Balaban RS. Power Grid Protection of the Muscle Mitochondrial Reticulum. Cell Rep. 2017 Apr 18;19(3):487-496. doi: 10.1016/j.celrep.2017.03.063. Erratum in: Cell Rep. 2018 May 29;23(9):2832. PMID: 28423313; PMCID: PMC5490369.