Mitochondrial creatine kinase: a major constituent of pathological inclusions seen in mitochondrial myopathies.

Abstract

Overaccumulation of abnormally organized mitochondria in so-called "ragged-red" skeletal muscle fibers Is a morphological hallmark of mitochondrial myopathies, in particular of mitochondrial encephalomyopathies. Characteristic for the abnormal mitochondria is the occurrence of highly ordered crystallineImmuno-electron microscopy revealed that these inclusions react heavily with specific antibodies against mitochondrial creatine kinase (Mi-CK). Image processing of selected crystalline inclusions, sectioned along the crystallographic b, c planes, resulted in an averaged picture displaying an arrangement of regular, square-shaped particles with a central cavity. The overall appearance, dimensions, and symmetry of these bullding blocks are very reminiscent of single isolated Mi-CK octamers. Taking these findins together, it is concluded that Mi-CK oiamers indeed represent the major, if not the only, component of these mitochondrial inclusions.The mitochondrial myopathies in which a defect in mitochondrial metabolism is thought to be the primary cause of the disease are clinically, biochemically, and genetically a heterogeneous group of disorders (1-3). For example, biochemical analysis reveals that respiratory chain deficiencies can be absent or vary from isolated defects to combined defects of several complexes of the chain (4, 5). To a varying degree, respiratory chain defects have also been reported in the so-called "encephalomyopathies"-i.e., in chronic progressive external ophthalmoplegia (CPEO), in Kearns-Sayre syndrome, in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), and in MERRF [myoclonus epilepsy with ragged-red fibers (RR fibers)] syndrome. All of these diseases are characterized by the presence of RR fibers in muscle biopsy specimens (1, 2).Characteristic aspects of the pathology in the RR fibers are an accumulation of abnormal and enlarged mitochondria and the occurrence in these mitochondria of highly ordered crystal-like inclusions, often referred to as "railway-track" or "parking lot" inclusions, within their intermembrane spaces (6, 7).Using optical diffraction techniques on thin muscle biopsy sections, the mitochondrial inclusions were shown to be true crystals (8). Two distinct types of crystals, type I (Fig. 1A) and type II (Fig. 1B), can be distinguished on the basis of shape, size, pattern, unit cell dimension, specific location of the crystals in the mitochondrial intermembrane space, and occurrence in different muscle fiber types. Understanding the role of the crystals in relation to the patient's pathology, either in terms of causative dysfunction or of mitochondrial response to a disease, requires a detailed knowledge of their chemical composition. Therefore, the biochemical and immunological nature ofthese inclusions has been studied using proteolytic digestion, enzyme cytochemistry, and immunogold labeling techniques. In addition, image processing of selected areas of these crystalline inclusions was performed to obtain more detailed s...

Coordinate Induction of Energy Gene Expression in Tissues of Mitochondrial Disease Patients

“…Ultrastructural studies have localized MtCK along the outer surface of the mitochondrial inner membrane, as well as at the contact sites between inner and outer mitochondrial membranes (46,47) where it is functionally coupled to the inner membrane ANT and the outer membrane porin (46,48). An increase in mMtCK mRNA would increase mMtCK protein, which is consistent with the finding that the PCI of RRFs contain crystallized mMtCK (17). MtCK crystalline inclusions can be induced in rat cardiomyocytes by growth in creatinedeficient medium (49).…”

“…Well defined protein synthesis mutations include the tRNA Leu(UUR) np 3243 A to G mutation associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) (MTTL1*MELAS3243G) (13)(14)(15) and the tRNA Lys np 8344 A to G mutation associated with myoclonic epilepsy and ragged red muscle fibers (MERRF) (MTTK*MERRF8993G) (9,16). Affected individuals harboring the MELAS and MERRF mutations frequently reveal a characteristic muscle histology that includes ragged red muscle fibers (RRFs) caused by the proliferation of abnormal mitochondria containing paracrystalline inclusions (PCI) (17).…”

A Complex II Defect Affects Mitochondrial Structure, Leading to ced-3- and ced-4-dependent Apoptosis and Aging

“…2D) or additional paracrystalline inclusions apparent in animals reared under 50% oxygen (Fig. 2E) may be mitochondrial creatine kinase (16). Perhaps even more importantly, ⌬⌿ m was severely compromised in mev-1 (Fig.…”

C-terminal Lysines Determine Phospholipid Interaction of Sarcomeric Mitochondrial Creatine Kinase

“…Under pathological conditions, these microcompartments can be disrupted, thus potentially leading to energy deficits and increased apoptosis (58 -60). Alternatively, MtCK overexpression in creatine-depleted mice (61) or patients with mitochondrial myopathies (62) leads to the formation of crystalline sheets between inner and outer mitochondrial membranes, as well as between cristae membranes. This corroborates the potential of MtCK to bind simultaneously to two membranes (27).…”