Mitochondrial Pathology: An Overview

Alterations of mitochondria are a common occurrence in spontaneous and experimentally induced disease processes (for a comprehensive review see Carafoli and Roman’). Although they are in general secondary to changes induced by the noxious agents elsewhere in the cell, in some cases primary mitochondrial alterations leading to systemic disturbances can be documented with certainty. Most are linked to genetic deficiencies in the membrane-bound or matrix-soluble enzymes (e.g., the enzymes of the oxidative and energy coupling systems or of the intramitochondrial portion of the urea cycle). However, other primitive deviations, e.g., those characterized by the production of auto-antibodies against mitochondrial components, are not genetic. The field of oncology deserves special attention even if a large portion of the observations in the literature on the relationship of mitochondria to malignancy concerns secondary phenomenology. In some rare tumors, admittedly benign in most cases, the enormous proliferation of mitochondria, unaccompanied by other obvious cellular disturbances, leaves the clear impression that mitochondria could be the primary, or a t least the most conspicuous target, of the oncogenic agent(s). And it may also be mentioned that recent studies on hexokinase and its relationship to mitochondria offer new support to the idea of mitochondrial defects as the primary response of cells to malignancyinducing agents. A comment is in order also on the matter of the mitochondrial Ca cycle, whose alterations are very common in cell pathology. Most likely, the disturbances of the cycle are not due to primary alterations of the CaZt uptake and/or the Ca2+ release transporters, but follow the deficiency of the plasma membrane Ca-filtering function. The result, however, will ultimately be a situation of stress for the mitochondrion, often at a stage when the remainder of the cell is still relatively unaffected. Since cell survival eventually depends on whether mitochondria will overcome the situation of stress, the deviations of the mitochondrial Ca cycle, even if not primitive, deserve a privileged place in a discussion of mitochondrial pathology. In the early days of mitochondrial pathology, most of the reports were by necessity morphological. They described a large number of peculiar mitochondrial alterations, particularly in muscle, among them bizarre shapes of the organelles, unusual orientations of the cristae, and especially crystalloids in the intracristal space or in the space between the inner and the outer membrane. The intramitochondrial crystalloids, e.g., those of the “parking lot” type in the intracrystal space (FIGURE l), are of obvious interest (they may correspond to the accumulation of mitochondrially made subunits of proteins assembled in collaboration with the cytoplasmic protein synthesis system) and deserve further study. However, a disproportionate emphasis has been placed in the past on their specificity. It is now known that they occasionally occur, together with the other alterations, in mitochondria of animals treated with various poisons, e.g., uncouplers of oxidative pho~phorylation,~ and even in normal mitochondria. “ In general, their occurrence in various disease conditions involving mitochondria is now thought to reflect the very limited range of options these organelles have in responding to noxious agents of various types with structural changes. The idea that structural