OPA1 protects intervertebral disc and knee joint health in aged mice by maintaining the structure and metabolic functions of mitochondria

Abstract

Due to their glycolytic nature and limited vascularity, nucleus pulposus (NP) cells of the intervertebral disc and articular chondrocytes were long thought to have minimal reliance on mitochondrial function. Recent studies have challenged this long-held view and highlighted the increasingly important role of mitochondria in the physiology of these tissues. We investigated the role of mitochondrial fusion protein OPA1 in maintaining the spine and knee joint health in aging mice. OPA1 knockdown in NP cells altered mitochondrial size and cristae shape and increased the oxygen consumption rate without affecting ATP synthesis. OPA1 governed the morphology of multiple organelles, and its loss resulted in the dysregulation of NP cell autophagy. Metabolic profiling and 13C-flux analyses revealed TCA cycle anaplerosis and altered metabolism in OPA1-deficient NP cells. Noteworthy, Opa1AcanCreERT2 mice showed age-dependent disc, and cartilage degeneration and vertebral osteopenia. Our findings suggest that OPA1 regulation of mitochondrial dynamics and multi-organelle interactions is critical in preserving metabolic homeostasis of disc and cartilage.

Tricarboxylic Acid Cycle Regulation of Metabolic Program, Redox System, and Epigenetic Remodeling for Bone Health and Disease

“…The TCA cycle is not only indispensable in the mitochondrial oxidative phosphorylation process for ATP production but is also important in catalyzing the biosynthesis of proteins, lipids, glucose, pyrimidine, and heme through anaplerotic reactions [21]. The use of 13 C-tracing analysis and high-throughput ultrahighperformance liquid chromatography-mass spectrometry for characterizing metabolomic landscapes and genetic or biochemical manipulation prompts us to understand the role each key enzyme or intermediate may play in bone cell function during skeletal tissue develop-ment and deterioration [22]. These enzymes or intermediates affect biological activities or metabolism in the bone microenvironment through canonical and non-canonical pathways.…”

“…Kafkia et al conduct 13 C-tracer analysis and proximity labelling mass spectrometry, identifying a plethora of TCA cycle routes, including glutamate-fumarate and citratesuccinate metabolism together with key enzymes present in the nucleus. The nuclear α-KG dehydrogenase produces succinyl-CoA, which promotes the succinylation of nuclear components to maintain the stemness of embryonic stem cells [75].…”

“…Bone mass homeostasis is a dynamic process of mineralized component turnover balanced by osteoblast/osteocyte-mediated bone formation [1] and osteoclastic resorption [1]. Osteoblasts produce key osteoclastogenic factors, such as receptor activator of nuclear factor-kB ligand (RANKL), inflammatory cytokines or chemokines, for coupling Antioxidants 2024, 13, 470 2 of 20 osteoclastic cells for bone remodeling [2]. Osteocytes play an important role in sclerostin production and transmit biomechanical or biophysical stimulation for bone mass homeostasis [1].…”

“…Key enzymes and intermediates of the TCA cycle exert canonical and noncanonical effects on bone-forming cells and osteoclasts, influencing bone physiology through biochemical and epigenetic pathways [12]. Plenty of in vivo models have shown that the genetic manipulation of these TCA cycle enzymes or biochemical control of the intermediates preserve bone tissue integrity, delaying degenerative bone or joint diseases [13].…”