Mitochondrial cytopathies are maternally inherited disorders of ATP production, with a predilection for primarily affecting the CNS. Many clinical phenotypes exist, each with varying involvement of skeletal and cardiac muscles, the kidneys and gastrointestinal system. Mitochondrial cytopathies can present early in life, but increasingly neurologists are faced with acute presentations of mitochondrial disease in adulthood. MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like syndrome) is a mitochondrial disorder that can present both insidiously and acutely. Common acute features are encephalopathy, seizures and metabolic strokes. This case series explores four patients who presented acutely with complications secondary to their MELAS. Through retrospective analysis of casenotes, the aim was to compare and contrast the clinical features and management of admissions, in the hope of understanding more about the ways these patients can acutely decompensate. Important findings include the multisystemic nature of acute admissions; sepsis as a trigger for metabolic crises; seizures that are characteristically refractory; the common occurrence of encephalopathy and psychosis; and a case of acute life-threatening hyponatraemia secondary to MELAS decompensation. Whilst these four patients demonstrate many valuable learning points about acute mitochondrial crises, the most striking is the widespread nature of organ involvement, which rarely seems to occur in isolation.